NM_000719.7:c.570C>T

Variant names:

• chr12-2449068-C-T
• rs372770722
• NM_000719.7:c.570C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000719.7(CACNA1C):​c.570C>T​(p.Tyr190Tyr) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000881 in 1,588,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ENSG00000285734 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 12-2449068-C-T is Benign according to our data. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449068-C-T is described in CliVar as Likely_benign. Clinvar id is 527063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.660C>T	p.Tyr220Tyr	synonymous_variant	Exon 4 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.660C>T	p.Tyr220Tyr	synonymous_variant	Exon 4 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.660C>T	p.Tyr220Tyr	synonymous_variant	Exon 4 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.660C>T	p.Tyr220Tyr	synonymous_variant	Exon 4 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.660C>T	p.Tyr220Tyr	synonymous_variant	Exon 4 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.660C>T	p.Tyr220Tyr	synonymous_variant	Exon 4 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.570C>T	p.Tyr190Tyr	synonymous_variant	Exon 4 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.519C>T	p.Tyr173Tyr	synonymous_variant	Exon 3 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.570C>T		non_coding_transcript_exon_variant	Exon 4 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000959 AC: 2 AN: 208644 AF XY: 0.00

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1436384 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 711970

African (AFR) AF: 0.0000903 AC: 3 AN: 33218

American (AMR) AF: 0.00 AC: 0 AN: 40370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.00 AC: 0 AN: 82616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097690

Other (OTH) AF: 0.0000168 AC: 1 AN: 59554

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.000241 AC: 10 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jan 15, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		7.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs372770722; hg19: chr12-2558234;