rs755280013

Positions:

chr12-2688619-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4BP6_ModerateBS2

The NM_000719.7(CACNA1C):c.5957G>A(p.Ser1986Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,866 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 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.30

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 (HGNC:):

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.41112703).

BP6

Variant 12-2688619-G-A is Benign according to our data. Variant chr12-2688619-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 411720.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.5957G>A	p.Ser1986Asn	missense_variant	46/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 linkuse as main transcript	c.5957G>A	p.Ser1986Asn	missense_variant	46/47	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.5957G>A	p.Ser1986Asn	missense_variant	46/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.5957G>A	p.Ser1986Asn	missense_variant	46/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 linkuse as main transcript	c.6296G>A	p.Ser2099Asn	missense_variant	49/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 linkuse as main transcript	c.6170G>A	p.Ser2057Asn	missense_variant	47/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 linkuse as main transcript	c.6137G>A	p.Ser2046Asn	missense_variant	46/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 linkuse as main transcript	c.6122G>A	p.Ser2041Asn	missense_variant	47/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 linkuse as main transcript	c.6101G>A	p.Ser2034Asn	missense_variant	48/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 linkuse as main transcript	c.6080G>A	p.Ser2027Asn	missense_variant	46/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 linkuse as main transcript	c.6062G>A	p.Ser2021Asn	missense_variant	47/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 linkuse as main transcript	c.6062G>A	p.Ser2021Asn	missense_variant	47/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 linkuse as main transcript	c.6047G>A	p.Ser2016Asn	missense_variant	46/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 linkuse as main transcript	c.6047G>A	p.Ser2016Asn	missense_variant	46/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 linkuse as main transcript	c.6047G>A	p.Ser2016Asn	missense_variant	46/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 linkuse as main transcript	c.6047G>A	p.Ser2016Asn	missense_variant	46/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 linkuse as main transcript	c.6041G>A	p.Ser2014Asn	missense_variant	47/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 linkuse as main transcript	c.6032G>A	p.Ser2011Asn	missense_variant	47/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 linkuse as main transcript	c.6017G>A	p.Ser2006Asn	missense_variant	47/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 linkuse as main transcript	c.6014G>A	p.Ser2005Asn	missense_variant	46/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 linkuse as main transcript	c.6014G>A	p.Ser2005Asn	missense_variant	46/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 linkuse as main transcript	c.6014G>A	p.Ser2005Asn	missense_variant	46/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 linkuse as main transcript	c.6008G>A	p.Ser2003Asn	missense_variant	46/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 linkuse as main transcript	c.5999G>A	p.Ser2000Asn	missense_variant	46/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 linkuse as main transcript	c.5981G>A	p.Ser1994Asn	missense_variant	45/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 linkuse as main transcript	c.5981G>A	p.Ser1994Asn	missense_variant	45/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 linkuse as main transcript	c.5975G>A	p.Ser1992Asn	missense_variant	45/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 linkuse as main transcript	c.5957G>A	p.Ser1986Asn	missense_variant	46/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 linkuse as main transcript	c.5957G>A	p.Ser1986Asn	missense_variant	46/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 linkuse as main transcript	c.5957G>A	p.Ser1986Asn	missense_variant	46/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 linkuse as main transcript	c.5957G>A	p.Ser1986Asn	missense_variant	46/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 linkuse as main transcript	c.5957G>A	p.Ser1986Asn	missense_variant	46/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 linkuse as main transcript	c.5948G>A	p.Ser1983Asn	missense_variant	46/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 linkuse as main transcript	c.5924G>A	p.Ser1975Asn	missense_variant	45/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

248836

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000621

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000702

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

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

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.41

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

-0.28

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.

REVEL

Benign

0.26

Sift

Uncertain

0.0060

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

Sift4G

Benign

0.17

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.99, 0.78, 0.96, 1.0, 1.0, 1.0

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

Vest4

0.59

MVP

0.73

MPC

0.44

ClinPred

0.38

GERP RS

5.2

gMVP

0.66

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