12-2550019-C-T

Variant names:

• chr12-2550019-C-T
• rs781074075
• NM_000719.7:c.1467C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.1467C>T​(p.Cys489Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,604,444 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0120
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 12-2550019-C-T is Benign according to our data. Variant chr12-2550019-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 527090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.012 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1557C>T	p.Cys519Cys	synonymous_variant	Exon 10 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1632C>T	p.Cys544Cys	synonymous_variant	Exon 11 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1557C>T	p.Cys519Cys	synonymous_variant	Exon 10 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1557C>T	p.Cys519Cys	synonymous_variant	Exon 10 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1557C>T	p.Cys519Cys	synonymous_variant	Exon 10 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1557C>T	p.Cys519Cys	synonymous_variant	Exon 10 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1542C>T	p.Cys514Cys	synonymous_variant	Exon 11 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1542C>T	p.Cys514Cys	synonymous_variant	Exon 11 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1458C>T	p.Cys486Cys	synonymous_variant	Exon 10 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1467C>T	p.Cys489Cys	synonymous_variant	Exon 10 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*74C>T		non_coding_transcript_exon_variant	Exon 8 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*74C>T		3_prime_UTR_variant	Exon 8 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000216 AC: 5 AN: 231064 AF XY: 0.0000399

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1452298 Hom.: 0 Cov.: 30 AF XY: 0.0000166 AC XY: 12 AN XY: 721434

African (AFR) AF: 0.0000900 AC: 3 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 43582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.0000763 AC: 3 AN: 39312

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1107294

Other (OTH) AF: 0.0000333 AC: 2 AN: 60054

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74306

African (AFR) AF: 0.0000965 AC: 4 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000181 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 19, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Apr 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jan 21, 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	-0.29
CADD	Benign	9.8
DANN	Benign	0.74
PhyloP100		0.012

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs781074075; hg19: chr12-2659185; COSMIC: COSV59769373;