rs765091519

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The NM_000719.7(CACNA1C):c.4068C>A(p.Ser1356Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1356S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.579

Publications

1 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 -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP6

Variant 12-2651762-C-A is Benign according to our data. Variant chr12-2651762-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 798433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.579 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.4302C>A	p.Ser1434Ser	synonymous_variant	Exon 34 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.4035C>A	p.Ser1345Ser	synonymous_variant	Exon 31 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.4233C>A	p.Ser1411Ser	synonymous_variant	Exon 33 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.4212C>A	p.Ser1404Ser	synonymous_variant	Exon 34 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.4134C>A	p.Ser1378Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4158C>A	p.Ser1386Ser	synonymous_variant	Exon 32 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.4158C>A	p.Ser1386Ser	synonymous_variant	Exon 32 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.4158C>A	p.Ser1386Ser	synonymous_variant	Exon 32 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.4158C>A	p.Ser1386Ser	synonymous_variant	Exon 32 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.4152C>A	p.Ser1384Ser	synonymous_variant	Exon 33 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.4143C>A	p.Ser1381Ser	synonymous_variant	Exon 33 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.4128C>A	p.Ser1376Ser	synonymous_variant	Exon 33 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.4119C>A	p.Ser1373Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.4110C>A	p.Ser1370Ser	synonymous_variant	Exon 32 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.4035C>A	p.Ser1345Ser	synonymous_variant	Exon 31 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.4035C>A	p.Ser1345Ser	synonymous_variant	Exon 31 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.4029C>A	p.Ser1343Ser	synonymous_variant	Exon 31 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.4068C>A	p.Ser1356Ser	synonymous_variant	Exon 32 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.4059C>A	p.Ser1353Ser	synonymous_variant	Exon 32 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.4035C>A	p.Ser1345Ser	synonymous_variant	Exon 31 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722026

African (AFR)

AF:

0.00

AC:

AN:

33384

American (AMR)

AF:

0.00

AC:

AN:

44484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

85522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106378

Other (OTH)

AF:

0.00

AC:

AN:

60056

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Nov 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 11, 2019

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

-0.26

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.58

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over