chr12-2677206-C-T

Position:

• chr12-2677206-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.4941C>T​(p.Asn1647Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,546 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 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.60

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 12-2677206-C-T is Benign according to our data. Variant chr12-2677206-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2677206-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5175C>T	p.Asn1725Asn	synonymous_variant	42/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4908C>T	p.Asn1636Asn	synonymous_variant	39/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5106C>T	p.Asn1702Asn	synonymous_variant	41/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5085C>T	p.Asn1695Asn	synonymous_variant	42/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5064C>T	p.Asn1688Asn	synonymous_variant	40/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5031C>T	p.Asn1677Asn	synonymous_variant	40/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5031C>T	p.Asn1677Asn	synonymous_variant	40/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5031C>T	p.Asn1677Asn	synonymous_variant	40/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5031C>T	p.Asn1677Asn	synonymous_variant	40/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5025C>T	p.Asn1675Asn	synonymous_variant	41/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5016C>T	p.Asn1672Asn	synonymous_variant	41/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5001C>T	p.Asn1667Asn	synonymous_variant	41/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4998C>T	p.Asn1666Asn	synonymous_variant	40/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4998C>T	p.Asn1666Asn	synonymous_variant	40/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4998C>T	p.Asn1666Asn	synonymous_variant	40/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4992C>T	p.Asn1664Asn	synonymous_variant	40/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4983C>T	p.Asn1661Asn	synonymous_variant	40/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4965C>T	p.Asn1655Asn	synonymous_variant	39/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4965C>T	p.Asn1655Asn	synonymous_variant	39/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4959C>T	p.Asn1653Asn	synonymous_variant	39/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4941C>T	p.Asn1647Asn	synonymous_variant	40/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4932C>T	p.Asn1644Asn	synonymous_variant	40/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4908C>T	p.Asn1636Asn	synonymous_variant	39/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000478

GnomAD3 exomes AF: 0.0000484 AC: 12 AN: 248190 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461360 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 726912

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000559 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 16, 2019

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.9
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs773832706; hg19: chr12-2786372; COSMIC: COSV59752478; COSMIC: COSV59752478;