12-2688637-G-T

Variant names:

• chr12-2688637-G-T
• rs375818733
• NM_000719.7:c.5975G>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.5975G>T​(p.Cys1992Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (1 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 7.47

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:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13849679).
• BP6: Variant 12-2688637-G-T is Benign according to our data. Variant chr12-2688637-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190628.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000191 (29/152216) while in subpopulation EAS AF= 0.000772 (4/5182). AF 95% confidence interval is 0.000399. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6314G>T	p.Cys2105Phe	missense_variant	Exon 49 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6188G>T	p.Cys2063Phe	missense_variant	Exon 47 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6155G>T	p.Cys2052Phe	missense_variant	Exon 46 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6140G>T	p.Cys2047Phe	missense_variant	Exon 47 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6119G>T	p.Cys2040Phe	missense_variant	Exon 48 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6098G>T	p.Cys2033Phe	missense_variant	Exon 46 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6080G>T	p.Cys2027Phe	missense_variant	Exon 47 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6080G>T	p.Cys2027Phe	missense_variant	Exon 47 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6065G>T	p.Cys2022Phe	missense_variant	Exon 46 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6065G>T	p.Cys2022Phe	missense_variant	Exon 46 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6065G>T	p.Cys2022Phe	missense_variant	Exon 46 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6065G>T	p.Cys2022Phe	missense_variant	Exon 46 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6059G>T	p.Cys2020Phe	missense_variant	Exon 47 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6050G>T	p.Cys2017Phe	missense_variant	Exon 47 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6035G>T	p.Cys2012Phe	missense_variant	Exon 47 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6032G>T	p.Cys2011Phe	missense_variant	Exon 46 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6032G>T	p.Cys2011Phe	missense_variant	Exon 46 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6032G>T	p.Cys2011Phe	missense_variant	Exon 46 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6026G>T	p.Cys2009Phe	missense_variant	Exon 46 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6017G>T	p.Cys2006Phe	missense_variant	Exon 46 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5999G>T	p.Cys2000Phe	missense_variant	Exon 45 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5999G>T	p.Cys2000Phe	missense_variant	Exon 45 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5993G>T	p.Cys1998Phe	missense_variant	Exon 45 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5975G>T	p.Cys1992Phe	missense_variant	Exon 46 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5966G>T	p.Cys1989Phe	missense_variant	Exon 46 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5942G>T	p.Cys1981Phe	missense_variant	Exon 45 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000926 AC: 23 AN: 248496 Hom.: 0 AF XY: 0.0000889 AC XY: 12 AN XY: 134992

Gnomad AFR exome AF: 0.000455

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000892

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461574 Hom.: 1 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 727090

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74368

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.000517 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000993 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Nov 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Uncertain:1

May 29, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jun 23, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA1C c.5975G>T; p.Cys1992Phe variant (rs375818733) is reported in the literature in an individual affected with ventricular fibrillation, but without a clear association with disease (Blancard 2018). This variant is reported in ClinVar (Variation ID: 190628), and is found in the general population with an overall allele frequency of 0.011% (30/279868 alleles) in the Genome Aggregation Database. The cysteine at codon 1992 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Functional analyses of the variant protein show no significant difference compared to wild type (Blancard 2018). However, due to limited information, the clinical significance of the p.Cys1992Phe variant is uncertain at this time. References: Blancard M et al. An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation. Sci Rep. 2018;8(1):14619. -

Long QT syndrome Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Sep 09, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Benign	0.26
Sift	Benign	0.030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;T
Polyphen		0.92, 0.72, 0.20, 0.24, 0.86, 0.97, 0.97, 0.23, 0.83, 0.98, 1.0	.;P;P;B;B;P;D;D;B;P;D;D;P;D;D;.;D;D;.;.;.;D;.
Vest4		0.83
MVP		0.63
MPC		0.68
ClinPred		0.19	T
GERP RS		5.0
gMVP		0.64

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: rs375818733; hg19: chr12-2797803;