rs757055492

Variant names:

• chr12-2493338-G-A
• rs757055492
• NM_000719.7:c.1065G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.1065G>A​(p.Thr355Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,028 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: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -7.21
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-2493338-G-A is Benign according to our data. Variant chr12-2493338-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.21 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.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1155G>A	p.Thr385Thr	synonymous_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1155G>A	p.Thr385Thr	synonymous_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1155G>A	p.Thr385Thr	synonymous_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1155G>A	p.Thr385Thr	synonymous_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1155G>A	p.Thr385Thr	synonymous_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1155G>A	p.Thr385Thr	synonymous_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1056G>A	p.Thr352Thr	synonymous_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1065G>A	p.Thr355Thr	synonymous_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.1002G>A	p.Thr334Thr	synonymous_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.1065G>A		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

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: 0.0000598 AC: 15 AN: 250890 AF XY: 0.0000589

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000492

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111962

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.0000724 AC: 3 AN: 41448

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

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 09, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

CACNA1C-related disorder Benign:1

May 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Nov 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Oct 02, 2019

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	-0.76
CADD	Benign	0.81
DANN	Benign	0.79
PhyloP100		-7.2
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs757055492; hg19: chr12-2602504; COSMIC: COSV59700237;