chr12-2686202-G-A

Position:

• chr12-2686202-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5717G>A​(p.Arg1906Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,613,930 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 6.42

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.20672476).
• BP6: Variant 12-2686202-G-A is Benign according to our data. Variant chr12-2686202-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402467.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5717G>A	p.Arg1906Gln	missense_variant	45/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5717G>A	p.Arg1906Gln	missense_variant	45/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5717G>A	p.Arg1906Gln	missense_variant	45/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5717G>A	p.Arg1906Gln	missense_variant	45/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6056G>A	p.Arg2019Gln	missense_variant	48/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5930G>A	p.Arg1977Gln	missense_variant	46/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5897G>A	p.Arg1966Gln	missense_variant	45/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5882G>A	p.Arg1961Gln	missense_variant	46/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5861G>A	p.Arg1954Gln	missense_variant	47/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5840G>A	p.Arg1947Gln	missense_variant	45/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5822G>A	p.Arg1941Gln	missense_variant	46/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5822G>A	p.Arg1941Gln	missense_variant	46/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5807G>A	p.Arg1936Gln	missense_variant	45/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5807G>A	p.Arg1936Gln	missense_variant	45/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5807G>A	p.Arg1936Gln	missense_variant	45/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5807G>A	p.Arg1936Gln	missense_variant	45/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5801G>A	p.Arg1934Gln	missense_variant	46/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5792G>A	p.Arg1931Gln	missense_variant	46/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5777G>A	p.Arg1926Gln	missense_variant	46/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5774G>A	p.Arg1925Gln	missense_variant	45/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5774G>A	p.Arg1925Gln	missense_variant	45/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5774G>A	p.Arg1925Gln	missense_variant	45/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5768G>A	p.Arg1923Gln	missense_variant	45/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5759G>A	p.Arg1920Gln	missense_variant	45/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5741G>A	p.Arg1914Gln	missense_variant	44/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5741G>A	p.Arg1914Gln	missense_variant	44/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5735G>A	p.Arg1912Gln	missense_variant	44/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5717G>A	p.Arg1906Gln	missense_variant	45/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5717G>A	p.Arg1906Gln	missense_variant	45/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5717G>A	p.Arg1906Gln	missense_variant	45/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5717G>A	p.Arg1906Gln	missense_variant	45/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5717G>A	p.Arg1906Gln	missense_variant	45/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5708G>A	p.Arg1903Gln	missense_variant	45/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5684G>A	p.Arg1895Gln	missense_variant	44/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000923 AC: 23 AN: 249308 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135252

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461600 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727090

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74504

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 20, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Arg1906Gln on HGMD transcript. Reported in 1 LQT proband -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 30, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31179551, 25184293, 23677916) -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 19, 2017

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2023

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_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.015	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.21	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	-0.55	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.027	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.73, 0.66, 0.97, 0.38, 0.88, 0.81, 0.020, 0.82, 0.88, 1.0, 0.85	.;P;P;D;B;P;P;P;B;P;P;P;P;D;P;.;P;P;.;.;.;P;.
Vest4		0.71
MVP		0.73
MPC		0.23
ClinPred		0.21	T
GERP RS		4.9
gMVP		0.67

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: rs758166168; hg19: chr12-2795368;