chr12-2679496-G-A

Position:

chr12-2679496-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_000719.7(CACNA1C):c.5144G>A(p.Arg1715Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,607,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.14

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 -4 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.

BP6

Variant 12-2679496-G-A is Benign according to our data. Variant chr12-2679496-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190685.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/47	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.5144G>A	p.Arg1715Gln	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 linkuse as main transcript	c.5378G>A	p.Arg1793Gln	missense_variant	44/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 linkuse as main transcript	c.5111G>A	p.Arg1704Gln	missense_variant	41/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 linkuse as main transcript	c.5309G>A	p.Arg1770Gln	missense_variant	43/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 linkuse as main transcript	c.5288G>A	p.Arg1763Gln	missense_variant	44/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 linkuse as main transcript	c.5267G>A	p.Arg1756Gln	missense_variant	42/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 linkuse as main transcript	c.5234G>A	p.Arg1745Gln	missense_variant	42/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 linkuse as main transcript	c.5234G>A	p.Arg1745Gln	missense_variant	42/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 linkuse as main transcript	c.5234G>A	p.Arg1745Gln	missense_variant	42/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 linkuse as main transcript	c.5234G>A	p.Arg1745Gln	missense_variant	42/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 linkuse as main transcript	c.5228G>A	p.Arg1743Gln	missense_variant	43/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 linkuse as main transcript	c.5219G>A	p.Arg1740Gln	missense_variant	43/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 linkuse as main transcript	c.5204G>A	p.Arg1735Gln	missense_variant	43/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 linkuse as main transcript	c.5201G>A	p.Arg1734Gln	missense_variant	42/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 linkuse as main transcript	c.5201G>A	p.Arg1734Gln	missense_variant	42/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 linkuse as main transcript	c.5201G>A	p.Arg1734Gln	missense_variant	42/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 linkuse as main transcript	c.5195G>A	p.Arg1732Gln	missense_variant	42/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 linkuse as main transcript	c.5186G>A	p.Arg1729Gln	missense_variant	42/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 linkuse as main transcript	c.5168G>A	p.Arg1723Gln	missense_variant	41/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 linkuse as main transcript	c.5168G>A	p.Arg1723Gln	missense_variant	41/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 linkuse as main transcript	c.5162G>A	p.Arg1721Gln	missense_variant	41/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 linkuse as main transcript	c.5144G>A	p.Arg1715Gln	missense_variant	42/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 linkuse as main transcript	c.5135G>A	p.Arg1712Gln	missense_variant	42/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 linkuse as main transcript	c.5111G>A	p.Arg1704Gln	missense_variant	41/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152148

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

241542

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000999

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1455144

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

722932

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000700

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000199

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2016

The R1715Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been observed in one other unrelated individual referred for Brugada syndrome genetic testing at GeneDx. This variant was not observed at a significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1715Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the R1715Q variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The p.R1715Q variant (also known as c.5144G>A), located in coding exon 42 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5144. The arginine at codon 1715 is replaced by glutamine, an amino acid with highly similar properties. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association with CACNA1C-related Timothy syndrome or long QT syndrome is unlikely. -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

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

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.57

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

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.1

.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.6

D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;D;D;D;D;N;D;D;.

REVEL

Uncertain

0.62

Sift

Benign

0.063

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;D;D;D;.

Sift4G

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

Polyphen

0.95, 0.053, 0.33, 0.092, 0.98, 0.98, 0.97, 0.12, 0.97, 0.97, 1.0, 0.98

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

Vest4

0.50

MVP

0.89

MPC

0.25

ClinPred

0.62

GERP RS

4.6

gMVP

0.50

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