rs368065584

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_000719.7(CACNA1C):c.1419C>A(p.Ser473Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S473S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.85

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP7

Synonymous conserved (PhyloP=-1.85 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1419C>A	p.Ser473Ser	synonymous_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.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1509C>A	p.Ser503Ser	synonymous_variant	Exon 10 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1584C>A	p.Ser528Ser	synonymous_variant	Exon 11 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1509C>A	p.Ser503Ser	synonymous_variant	Exon 10 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1509C>A	p.Ser503Ser	synonymous_variant	Exon 10 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1509C>A	p.Ser503Ser	synonymous_variant	Exon 10 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1509C>A	p.Ser503Ser	synonymous_variant	Exon 10 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1494C>A	p.Ser498Ser	synonymous_variant	Exon 11 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1494C>A	p.Ser498Ser	synonymous_variant	Exon 11 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1410C>A	p.Ser470Ser	synonymous_variant	Exon 10 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1419C>A	p.Ser473Ser	synonymous_variant	Exon 10 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*26C>A		non_coding_transcript_exon_variant	Exon 8 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*26C>A		3_prime_UTR_variant	Exon 8 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722812

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33364

American (AMR)

AF:

0.00

AC:

AN:

43896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39418

South Asian (SAS)

AF:

0.00

AC:

AN:

84456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52914

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108788

Other (OTH)

AF:

0.00

AC:

AN:

60152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.85

(source)

DANN

Benign

0.85

PhyloP100

-1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Computational scores

Splicing

Publications

Other links and lift over