rs776242172

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000719.7(CACNA1C):c.1381C>A(p.Pro461Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 1,450,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P461A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.46

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1372C>A	p.Pro458Thr	missense_variant	Exon 9 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.1113+19589C>A		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000439

AC:

AN:

227536

AF XY:

0.00000815

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000980

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000897

AC:

AN:

1450002

Hom.:

Cov.:

AF XY:

0.00000694

AC XY:

AN XY:

719986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33302

American (AMR)

AF:

0.00

AC:

AN:

43106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.00

AC:

AN:

39300

South Asian (SAS)

AF:

0.00

AC:

AN:

83764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52644

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1106306

Other (OTH)

AF:

0.0000167

AC:

AN:

60006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 12, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Long QT syndrome

Uncertain:1

Oct 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline with threonine at codon 461 of the CACNA1C protein (p.Pro461Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs776242172, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 456945). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

CardioboostArm

Uncertain

0.16

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

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

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.64

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

0.70

MutationAssessor

Benign

1.4

.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.7

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

REVEL

Uncertain

0.61

Sift

Benign

0.24

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

Sift4G

Benign

0.17

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

Polyphen

1.0, 0.028, 0.85, 0.61, 0.11

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

Vest4

0.73

MutPred

0.27

Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);

MVP

0.89

MPC

2.1

ClinPred

0.95

GERP RS

4.4

gMVP

0.93

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over