12-2449035-C-T

Variant names:

• chr12-2449035-C-T
• rs369673473
• NM_000719.7:c.537C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.537C>T​(p.Ile179Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000837 in 1,601,044 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I179I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0690
• 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

ENSG00000285734 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 12-2449035-C-T is Benign according to our data. Variant chr12-2449035-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 308128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.069 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000434 (66/152152) while in subpopulation AFR AF = 0.00133 (55/41422). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.537C>T	p.Ile179Ile	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.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.627C>T	p.Ile209Ile	synonymous_variant	Exon 4 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.627C>T	p.Ile209Ile	synonymous_variant	Exon 4 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.627C>T	p.Ile209Ile	synonymous_variant	Exon 4 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.627C>T	p.Ile209Ile	synonymous_variant	Exon 4 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.627C>T	p.Ile209Ile	synonymous_variant	Exon 4 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.627C>T	p.Ile209Ile	synonymous_variant	Exon 4 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.537C>T	p.Ile179Ile	synonymous_variant	Exon 4 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.486C>T	p.Ile162Ile	synonymous_variant	Exon 3 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.537C>T		non_coding_transcript_exon_variant	Exon 4 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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: 0.000115 AC: 27 AN: 235418 AF XY: 0.000102

Gnomad AFR exome AF: 0.000881

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 68 AN: 1448892 Hom.: 0 Cov.: 28 AF XY: 0.0000389 AC XY: 28 AN XY: 720222

African (AFR) AF: 0.00108 AC: 36 AN: 33342

American (AMR) AF: 0.000161 AC: 7 AN: 43556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 84672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53060

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00000997 AC: 11 AN: 1103034

Other (OTH) AF: 0.000100 AC: 6 AN: 59976

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74316

African (AFR) AF: 0.00133 AC: 55 AN: 41422

American (AMR) AF: 0.000654 AC: 10 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

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

Alfa AF: 0.000461 Hom.: 0

Bravo AF: 0.000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Oct 26, 2016

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	-0.32
CADD	Benign	12
DANN	Benign	0.84
PhyloP100		0.069

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: rs369673473; hg19: chr12-2558201; COSMIC: COSV59717579;