12-2677840-C-T

Position:

• chr12-2677840-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.5064C>T​(p.Ser1688Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,613,984 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (8 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.104

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 12-2677840-C-T is Benign according to our data. Variant chr12-2677840-C-T is described in ClinVar as [Benign]. Clinvar id is 136630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2677840-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00411 (626/152308) while in subpopulation AFR AF= 0.0144 (600/41562). AF 95% confidence interval is 0.0135. There are 3 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 626 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5298C>T	p.Ser1766Ser	synonymous_variant	43/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5031C>T	p.Ser1677Ser	synonymous_variant	40/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5229C>T	p.Ser1743Ser	synonymous_variant	42/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5208C>T	p.Ser1736Ser	synonymous_variant	43/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5187C>T	p.Ser1729Ser	synonymous_variant	41/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5154C>T	p.Ser1718Ser	synonymous_variant	41/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5154C>T	p.Ser1718Ser	synonymous_variant	41/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5154C>T	p.Ser1718Ser	synonymous_variant	41/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5154C>T	p.Ser1718Ser	synonymous_variant	41/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5148C>T	p.Ser1716Ser	synonymous_variant	42/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5139C>T	p.Ser1713Ser	synonymous_variant	42/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5124C>T	p.Ser1708Ser	synonymous_variant	42/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5121C>T	p.Ser1707Ser	synonymous_variant	41/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5121C>T	p.Ser1707Ser	synonymous_variant	41/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5121C>T	p.Ser1707Ser	synonymous_variant	41/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5115C>T	p.Ser1705Ser	synonymous_variant	41/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5106C>T	p.Ser1702Ser	synonymous_variant	41/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5088C>T	p.Ser1696Ser	synonymous_variant	40/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5088C>T	p.Ser1696Ser	synonymous_variant	40/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5082C>T	p.Ser1694Ser	synonymous_variant	40/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5064C>T	p.Ser1688Ser	synonymous_variant	41/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5055C>T	p.Ser1685Ser	synonymous_variant	41/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5031C>T	p.Ser1677Ser	synonymous_variant	40/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 626 AN: 152190 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00116 AC: 290 AN: 249224 Hom.: 4 AF XY: 0.000888 AC XY: 120 AN XY: 135206

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000465 AC: 679 AN: 1461676 Hom.: 8 Cov.: 31 AF XY: 0.000386 AC XY: 281 AN XY: 727126

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152308 Hom.: 3 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74466

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00200 Hom.: 1

Bravo AF: 0.00550

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2015	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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2020	- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2015

This alteration is classified as 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	0.75

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: rs139872789; hg19: chr12-2787006; COSMIC: COSV59781486; COSMIC: COSV59781486;