12-2549962-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000719.7(CACNA1C):c.1410G>T(p.Glu470Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. E470G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31952465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1575G>T	p.Glu525Asp	missense_variant	Exon 11 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1485G>T	p.Glu495Asp	missense_variant	Exon 11 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1485G>T	p.Glu495Asp	missense_variant	Exon 11 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1401G>T	p.Glu467Asp	missense_variant	Exon 10 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*17G>T		non_coding_transcript_exon_variant	Exon 8 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*17G>T		3_prime_UTR_variant	Exon 8 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1452956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721762

African (AFR)

AF:

0.00

AC:

AN:

33332

American (AMR)

AF:

0.00

AC:

AN:

43600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.00

AC:

AN:

39346

South Asian (SAS)

AF:

0.00

AC:

AN:

84134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107888

Other (OTH)

AF:

0.00

AC:

AN:

60114

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Dec 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid with aspartic acid at codon 470 of the CACNA1C protein (p.Glu470Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

Uncertain

0.37

CardioboostArm

Benign

0.0000011

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

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

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.32

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

0.59

MutationAssessor

Benign

0.0

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

PhyloP100

3.6

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.7

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

REVEL

Uncertain

0.55

Sift

Benign

0.34

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

0.38

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

Vest4

0.49

ClinPred

0.58

GERP RS

5.1

gMVP

0.79

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over