12-2691057-G-C

Position:

chr12-2691057-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_000719.7(CACNA1C):c.6275G>C(p.Gly2092Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000809 in 1,607,452 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.41

Variant links:

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 links:

CACNA1C-AS1 (HGNC:):

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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=0.27090472).

BP6

Variant 12-2691057-G-C is Benign according to our data. Variant chr12-2691057-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411716.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 linkuse as main transcript	c.6614G>C	p.Gly2205Ala	missense_variant	50/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 linkuse as main transcript	c.6488G>C	p.Gly2163Ala	missense_variant	48/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 linkuse as main transcript	c.6455G>C	p.Gly2152Ala	missense_variant	47/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 linkuse as main transcript	c.6440G>C	p.Gly2147Ala	missense_variant	48/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 linkuse as main transcript	c.6419G>C	p.Gly2140Ala	missense_variant	49/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 linkuse as main transcript	c.6398G>C	p.Gly2133Ala	missense_variant	47/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 linkuse as main transcript	c.6380G>C	p.Gly2127Ala	missense_variant	48/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 linkuse as main transcript	c.6380G>C	p.Gly2127Ala	missense_variant	48/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 linkuse as main transcript	c.6365G>C	p.Gly2122Ala	missense_variant	47/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 linkuse as main transcript	c.6365G>C	p.Gly2122Ala	missense_variant	47/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 linkuse as main transcript	c.6365G>C	p.Gly2122Ala	missense_variant	47/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 linkuse as main transcript	c.6365G>C	p.Gly2122Ala	missense_variant	47/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 linkuse as main transcript	c.6359G>C	p.Gly2120Ala	missense_variant	48/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 linkuse as main transcript	c.6350G>C	p.Gly2117Ala	missense_variant	48/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 linkuse as main transcript	c.6335G>C	p.Gly2112Ala	missense_variant	48/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 linkuse as main transcript	c.6332G>C	p.Gly2111Ala	missense_variant	47/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 linkuse as main transcript	c.6332G>C	p.Gly2111Ala	missense_variant	47/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 linkuse as main transcript	c.6332G>C	p.Gly2111Ala	missense_variant	47/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 linkuse as main transcript	c.6326G>C	p.Gly2109Ala	missense_variant	47/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 linkuse as main transcript	c.6317G>C	p.Gly2106Ala	missense_variant	47/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 linkuse as main transcript	c.6299G>C	p.Gly2100Ala	missense_variant	46/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 linkuse as main transcript	c.6299G>C	p.Gly2100Ala	missense_variant	46/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 linkuse as main transcript	c.6293G>C	p.Gly2098Ala	missense_variant	46/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 linkuse as main transcript	c.6275G>C	p.Gly2092Ala	missense_variant	47/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 linkuse as main transcript	c.6266G>C	p.Gly2089Ala	missense_variant	47/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 linkuse as main transcript	c.6242G>C	p.Gly2081Ala	missense_variant	46/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000430

AC:

AN:

232592

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127046

show subpopulations

Gnomad AFR exome

AF:

0.0000748

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000550

AC:

AN:

1455294

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

723408

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The p.G2092A variant (also known as c.6275G>C), located in coding exon 47 of the CACNA1C gene, results from a G to C substitution at nucleotide position 6275. The glycine at codon 2092 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of Timothy syndrome or long QT syndrome; however, its contribution to the development of CACNA1C-related neurodevelopmental disorder is uncertain. -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.83

M_CAP

Benign

0.031

MetaRNN

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

MetaSVM

Benign

-0.65

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.9

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

REVEL

Benign

0.20

Sift

Uncertain

0.0050

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.0080

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 0.80, 0.82, 0.090, 1.0, 0.84, 0.99, 0.40

.;D;P;P;B;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;B;.

Vest4

0.38

MVP

0.70

MPC

0.36

ClinPred

0.86

GERP RS

4.5

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over