12-2685762-G-A

Position:

chr12-2685762-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000719.7(CACNA1C):c.5600G>A(p.Arg1867Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,718 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.17

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:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the 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=0.13743314).

BP6

Variant 12-2685762-G-A is Benign according to our data. Variant chr12-2685762-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 518667.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.5939G>A	p.Arg1980Gln	missense_variant	47/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.5813G>A	p.Arg1938Gln	missense_variant	45/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.5780G>A	p.Arg1927Gln	missense_variant	44/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.5765G>A	p.Arg1922Gln	missense_variant	45/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.5744G>A	p.Arg1915Gln	missense_variant	46/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.5723G>A	p.Arg1908Gln	missense_variant	44/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.5705G>A	p.Arg1902Gln	missense_variant	45/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.5705G>A	p.Arg1902Gln	missense_variant	45/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.5690G>A	p.Arg1897Gln	missense_variant	44/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.5690G>A	p.Arg1897Gln	missense_variant	44/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.5690G>A	p.Arg1897Gln	missense_variant	44/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.5690G>A	p.Arg1897Gln	missense_variant	44/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.5684G>A	p.Arg1895Gln	missense_variant	45/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5675G>A	p.Arg1892Gln	missense_variant	45/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5660G>A	p.Arg1887Gln	missense_variant	45/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5657G>A	p.Arg1886Gln	missense_variant	44/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5657G>A	p.Arg1886Gln	missense_variant	44/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5657G>A	p.Arg1886Gln	missense_variant	44/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5651G>A	p.Arg1884Gln	missense_variant	44/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5642G>A	p.Arg1881Gln	missense_variant	44/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5624G>A	p.Arg1875Gln	missense_variant	43/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5624G>A	p.Arg1875Gln	missense_variant	43/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5618G>A	p.Arg1873Gln	missense_variant	43/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5600G>A	p.Arg1867Gln	missense_variant	44/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5591G>A	p.Arg1864Gln	missense_variant	44/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5567G>A	p.Arg1856Gln	missense_variant	43/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

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:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

248922

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135052

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 25, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1867 of the CACNA1C protein (p.Arg1867Gln). This variant is present in population databases (rs535350857, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 518667). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The p.R1867Q variant (also known as c.5600G>A), located in coding exon 44 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5600. The arginine at codon 1867 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

CACNA1C: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

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

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.065

MetaRNN

Benign

0.14

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

-0.67

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.91

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

REVEL

Benign

0.15

Sift

Benign

0.12

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

Sift4G

Benign

0.33

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, 0.062, 0.93, 0.33, 0.96, 0.97, 0.80, 0.65, 0.98, 0.89, 1.0, 0.88

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

Vest4

0.40

MVP

0.63

MPC

0.43

ClinPred

0.54

GERP RS

4.3

gMVP

0.37

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

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