rs377173101

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):c.4128G>A(p.Val1376Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,752 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.851

Publications

2 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: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 12-2653888-G-A is Benign according to our data. Variant chr12-2653888-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 384026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.851 with no splicing effect.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.4362G>A	p.Val1454Val	synonymous_variant	Exon 35 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.4095G>A	p.Val1365Val	synonymous_variant	Exon 32 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.4293G>A	p.Val1431Val	synonymous_variant	Exon 34 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.4272G>A	p.Val1424Val	synonymous_variant	Exon 35 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.4194G>A	p.Val1398Val	synonymous_variant	Exon 33 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4218G>A	p.Val1406Val	synonymous_variant	Exon 33 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.4218G>A	p.Val1406Val	synonymous_variant	Exon 33 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.4218G>A	p.Val1406Val	synonymous_variant	Exon 33 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.4218G>A	p.Val1406Val	synonymous_variant	Exon 33 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.4212G>A	p.Val1404Val	synonymous_variant	Exon 34 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.4203G>A	p.Val1401Val	synonymous_variant	Exon 34 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.4188G>A	p.Val1396Val	synonymous_variant	Exon 34 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.4179G>A	p.Val1393Val	synonymous_variant	Exon 33 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.4170G>A	p.Val1390Val	synonymous_variant	Exon 33 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.4095G>A	p.Val1365Val	synonymous_variant	Exon 32 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.4095G>A	p.Val1365Val	synonymous_variant	Exon 32 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.4089G>A	p.Val1363Val	synonymous_variant	Exon 32 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.4128G>A	p.Val1376Val	synonymous_variant	Exon 33 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.4119G>A	p.Val1373Val	synonymous_variant	Exon 33 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.4095G>A	p.Val1365Val	synonymous_variant	Exon 32 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000563

AC:

AN:

248704

AF XY:

0.0000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461558

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111830

Other (OTH)

AF:

0.000133

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000682

Hom.:

Bravo

AF:

0.0000831

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 11, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1C: BP4, BP7 -

Long QT syndrome

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 24, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.85

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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