rs535291848

Positions:

• chr12-2688688-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4 BP6_Very_Strong BS2

The NM_000719.7(CACNA1C):​c.6026G>A​(p.Arg2009Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,612,584 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 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.66

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.

• 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=0.2981665).
• BP6: Variant 12-2688688-G-A is Benign according to our data. Variant chr12-2688688-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 527022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6026G>A	p.Arg2009Gln	missense_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6026G>A	p.Arg2009Gln	missense_variant	46/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6026G>A	p.Arg2009Gln	missense_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6026G>A	p.Arg2009Gln	missense_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6365G>A	p.Arg2122Gln	missense_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6239G>A	p.Arg2080Gln	missense_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6206G>A	p.Arg2069Gln	missense_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6191G>A	p.Arg2064Gln	missense_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6170G>A	p.Arg2057Gln	missense_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6149G>A	p.Arg2050Gln	missense_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6131G>A	p.Arg2044Gln	missense_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6131G>A	p.Arg2044Gln	missense_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6116G>A	p.Arg2039Gln	missense_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6116G>A	p.Arg2039Gln	missense_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6116G>A	p.Arg2039Gln	missense_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6116G>A	p.Arg2039Gln	missense_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6110G>A	p.Arg2037Gln	missense_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6101G>A	p.Arg2034Gln	missense_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6086G>A	p.Arg2029Gln	missense_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6083G>A	p.Arg2028Gln	missense_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6083G>A	p.Arg2028Gln	missense_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6083G>A	p.Arg2028Gln	missense_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6077G>A	p.Arg2026Gln	missense_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6068G>A	p.Arg2023Gln	missense_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6050G>A	p.Arg2017Gln	missense_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6050G>A	p.Arg2017Gln	missense_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6044G>A	p.Arg2015Gln	missense_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6026G>A	p.Arg2009Gln	missense_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6026G>A	p.Arg2009Gln	missense_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6026G>A	p.Arg2009Gln	missense_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6026G>A	p.Arg2009Gln	missense_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6026G>A	p.Arg2009Gln	missense_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6017G>A	p.Arg2006Gln	missense_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5993G>A	p.Arg1998Gln	missense_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000287 AC: 7 AN: 244034 Hom.: 0 AF XY: 0.0000376 AC XY: 5 AN XY: 132992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1460300 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 726474

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2022

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	-0.25	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.19
Sift	Benign	0.055	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;D;D;.
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.97, 0.93, 0.89, 0.068, 1.0, 0.98, 0.99, 0.60, 1.0, 0.81	.;D;P;P;B;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;P;.
Vest4		0.62
MVP		0.62
MPC		0.23
ClinPred		0.45	T
GERP RS		5.2
gMVP		0.56

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: rs535291848; hg19: chr12-2797854; COSMIC: COSV59756504; COSMIC: COSV59756504;