rs552478740

Positions:

• chr12-2688663-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000719.7(CACNA1C):​c.6001G>A​(p.Gly2001Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.08

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 -8 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=0.06362143).
• BP6: Variant 12-2688663-G-A is Benign according to our data. Variant chr12-2688663-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575699.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6001G>A	p.Gly2001Ser	missense_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6001G>A	p.Gly2001Ser	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.6001G>A	p.Gly2001Ser	missense_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6001G>A	p.Gly2001Ser	missense_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6340G>A	p.Gly2114Ser	missense_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6214G>A	p.Gly2072Ser	missense_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6181G>A	p.Gly2061Ser	missense_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6166G>A	p.Gly2056Ser	missense_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6145G>A	p.Gly2049Ser	missense_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6124G>A	p.Gly2042Ser	missense_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6106G>A	p.Gly2036Ser	missense_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6106G>A	p.Gly2036Ser	missense_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6091G>A	p.Gly2031Ser	missense_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6091G>A	p.Gly2031Ser	missense_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6091G>A	p.Gly2031Ser	missense_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6091G>A	p.Gly2031Ser	missense_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6085G>A	p.Gly2029Ser	missense_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6076G>A	p.Gly2026Ser	missense_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6061G>A	p.Gly2021Ser	missense_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6058G>A	p.Gly2020Ser	missense_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6058G>A	p.Gly2020Ser	missense_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6058G>A	p.Gly2020Ser	missense_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6052G>A	p.Gly2018Ser	missense_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6043G>A	p.Gly2015Ser	missense_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6025G>A	p.Gly2009Ser	missense_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6025G>A	p.Gly2009Ser	missense_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6019G>A	p.Gly2007Ser	missense_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6001G>A	p.Gly2001Ser	missense_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6001G>A	p.Gly2001Ser	missense_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6001G>A	p.Gly2001Ser	missense_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6001G>A	p.Gly2001Ser	missense_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6001G>A	p.Gly2001Ser	missense_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5992G>A	p.Gly1998Ser	missense_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5968G>A	p.Gly1990Ser	missense_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000566 AC: 14 AN: 247140 Hom.: 0 AF XY: 0.0000818 AC XY: 11 AN XY: 134436

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000716

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461296 Hom.: 0 Cov.: 33 AF XY: 0.0000385 AC XY: 28 AN XY: 726976

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74478

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000580 AC: 7

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 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	-0.17	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.017	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.085	N
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.064	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	-0.26	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.30	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.27
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010, 0.26, 0.16, 0.43, 0.041	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.20
MVP		0.43
MPC		0.19
ClinPred		0.013	T
GERP RS		0.97
gMVP		0.32

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: rs552478740; hg19: chr12-2797829; COSMIC: COSV59776235; COSMIC: COSV59776235;