rs757966245

Positions:

chr12-2674532-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001129829.2(CACNA1C):c.4841G>A(p.Arg1614His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,554,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 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 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

CACNA1C
NM_001129829.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.589

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 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 7.1751 (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=0.05975932).

BP6

Variant 12-2674532-G-A is Benign according to our data. Variant chr12-2674532-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190618.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

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 linkuse as main transcript	c.4727-9G>A		intron_variant		ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 linkuse as main transcript	c.4727-9G>A		intron_variant		ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000344100.7 linkuse as main transcript	c.4841G>A	p.Arg1614His	missense_variant	39/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000399621.5 linkuse as main transcript	c.4775G>A	p.Arg1592His	missense_variant	39/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 linkuse as main transcript	c.4775G>A	p.Arg1592His	missense_variant	39/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 linkuse as main transcript	c.4775G>A	p.Arg1592His	missense_variant	39/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399591.5 linkuse as main transcript	c.4742G>A	p.Arg1581His	missense_variant	38/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 linkuse as main transcript	c.4742G>A	p.Arg1581His	missense_variant	38/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 linkuse as main transcript	c.4736G>A	p.Arg1579His	missense_variant	38/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.4727-9G>A		intron_variant		5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.4727-9G>A		intron_variant		1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 linkuse as main transcript	c.4961-9G>A		intron_variant				ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 linkuse as main transcript	c.4727-9G>A		intron_variant		5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 linkuse as main transcript	c.4694-9G>A		intron_variant		5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 linkuse as main transcript	c.4892-9G>A		intron_variant				ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 linkuse as main transcript	c.4871-9G>A		intron_variant		1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000327702.12 linkuse as main transcript	c.4727-9G>A		intron_variant		1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 linkuse as main transcript	c.4727-9G>A		intron_variant		5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 linkuse as main transcript	c.4817-9G>A		intron_variant				ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 linkuse as main transcript	c.4817-9G>A		intron_variant				ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 linkuse as main transcript	c.4817-9G>A		intron_variant				ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 linkuse as main transcript	c.4817-9G>A		intron_variant				ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 linkuse as main transcript	c.4811-9G>A		intron_variant		1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 linkuse as main transcript	c.4802-9G>A		intron_variant		5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 linkuse as main transcript	c.4787-9G>A		intron_variant		1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399629.5 linkuse as main transcript	c.4778-9G>A		intron_variant		1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 linkuse as main transcript	c.4769-9G>A		intron_variant				ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399597.5 linkuse as main transcript	c.4727-9G>A		intron_variant		1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 linkuse as main transcript	c.4727-9G>A		intron_variant		1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 linkuse as main transcript	c.4727-9G>A		intron_variant		1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 linkuse as main transcript	c.4727-9G>A		intron_variant		1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 linkuse as main transcript	c.4727-9G>A		intron_variant				ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 linkuse as main transcript	c.4718-9G>A		intron_variant				ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 linkuse as main transcript	c.4694-9G>A		intron_variant				ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000366

AC:

AN:

163974

Hom.:

AF XY:

0.0000462

AC XY:

AN XY:

86662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000854

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000767

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000299

AC:

AN:

1402646

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

692200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000277

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000296

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.000105

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000160

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000435

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Timothy syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2018

- -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.9

DANN

Benign

0.92

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.021

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.060

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

MetaSVM

Uncertain

-0.27

PROVEAN

Benign

-0.12

N;N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0050

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

Sift4G

Benign

0.061

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

Polyphen

0.0

B;B;B;B;B;B;B

Vest4

0.062

MutPred

0.35

.;.;.;.;Gain of catalytic residue at F1613 (P = 0.0072);.;.;

MVP

0.31

ClinPred

0.034

GERP RS

-8.6

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