rs199538058

Positions:

• chr12-2679566-C-A
• chr12-2679566-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.5214C>A​(p.Gly1738Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,558 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1738G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -2.60

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-2679566-C-A is Benign according to our data. Variant chr12-2679566-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136632.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr12-2679566-C-A is described in Lovd as [Benign]. Variant chr12-2679566-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00114 (173/152350) while in subpopulation NFE AF= 0.00169 (115/68028). AF 95% confidence interval is 0.00144. There are 1 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 173 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5448C>A	p.Gly1816Gly	synonymous_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5181C>A	p.Gly1727Gly	synonymous_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5379C>A	p.Gly1793Gly	synonymous_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5358C>A	p.Gly1786Gly	synonymous_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5337C>A	p.Gly1779Gly	synonymous_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5304C>A	p.Gly1768Gly	synonymous_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5304C>A	p.Gly1768Gly	synonymous_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5304C>A	p.Gly1768Gly	synonymous_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5304C>A	p.Gly1768Gly	synonymous_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5298C>A	p.Gly1766Gly	synonymous_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5289C>A	p.Gly1763Gly	synonymous_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5274C>A	p.Gly1758Gly	synonymous_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5271C>A	p.Gly1757Gly	synonymous_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5271C>A	p.Gly1757Gly	synonymous_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5271C>A	p.Gly1757Gly	synonymous_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5265C>A	p.Gly1755Gly	synonymous_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5256C>A	p.Gly1752Gly	synonymous_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5238C>A	p.Gly1746Gly	synonymous_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5238C>A	p.Gly1746Gly	synonymous_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5232C>A	p.Gly1744Gly	synonymous_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5214C>A	p.Gly1738Gly	synonymous_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5205C>A	p.Gly1735Gly	synonymous_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5181C>A	p.Gly1727Gly	synonymous_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00127 AC: 313 AN: 247232 Hom.: 0 AF XY: 0.00132 AC XY: 178 AN XY: 134350

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.000553

Gnomad ASJ exome AF: 0.00701

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00134 AC: 1965 AN: 1461208 Hom.: 3 Cov.: 31 AF XY: 0.00139 AC XY: 1009 AN XY: 726874

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000694

Gnomad4 ASJ exome AF: 0.00713

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74496

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00118

EpiCase AF: 0.00180

EpiControl AF: 0.00226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CACNA1C: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2015

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	-0.39
CADD	Benign	0.28
DANN	Benign	0.86

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: rs199538058; hg19: chr12-2788732;