rs1544514

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The ENST00000399655.6(CACNA1C):c.522G>A(p.Ala174=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,603,596 control chromosomes in the GnomAD database, including 31,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2420 hom., cov: 33)

Exomes 𝑓: 0.20 ( 29079 hom. )

Consequence

CACNA1C
ENST00000399655.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0370

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 12-2449020-G-A is Benign according to our data. Variant chr12-2449020-G-A is described in ClinVar as [Benign]. Clinvar id is 93412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449020-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.037 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.522G>A	p.Ala174=	synonymous_variant	4/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.522G>A	p.Ala174=	synonymous_variant	4/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.522G>A	p.Ala174=	synonymous_variant	4/47	5	NM_001167623.2	ENSP00000382512	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.522G>A	p.Ala174=	synonymous_variant	4/47	1	NM_000719.7	ENSP00000382563	Q13936-12
	ENST00000649808.1 linkuse as main transcript	n.208+133C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25617

AN:

151994

Hom.:

2420

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0971

Gnomad AMI

AF:

0.315

Gnomad AMR

AF:

0.185

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.0615

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.167

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.171

GnomAD3 exomes

AF:

0.176

AC:

42748

AN:

242448

Hom.:

4157

AF XY:

0.179

AC XY:

23507

AN XY:

131480

show subpopulations

Gnomad AFR exome

AF:

0.0951

Gnomad AMR exome

AF:

0.159

Gnomad ASJ exome

AF:

0.290

Gnomad EAS exome

AF:

0.0644

Gnomad SAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.164

Gnomad NFE exome

AF:

0.209

Gnomad OTH exome

AF:

0.202

GnomAD4 exome

AF:

0.196

AC:

284454

AN:

1451484

Hom.:

29079

Cov.:

AF XY:

0.196

AC XY:

141705

AN XY:

722124

show subpopulations

Gnomad4 AFR exome

AF:

0.0942

Gnomad4 AMR exome

AF:

0.160

Gnomad4 ASJ exome

AF:

0.285

Gnomad4 EAS exome

AF:

0.0719

Gnomad4 SAS exome

AF:

0.150

Gnomad4 FIN exome

AF:

0.166

Gnomad4 NFE exome

AF:

0.208

Gnomad4 OTH exome

AF:

0.190

GnomAD4 genome

AF:

0.168

AC:

25623

AN:

152112

Hom.:

2420

Cov.:

AF XY:

0.166

AC XY:

12325

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0970

Gnomad4 AMR

AF:

0.184

Gnomad4 ASJ

AF:

0.291

Gnomad4 EAS

AF:

0.0617

Gnomad4 SAS

AF:

0.147

Gnomad4 FIN

AF:

0.167

Gnomad4 NFE

AF:

0.210

Gnomad4 OTH

AF:

0.168

Alfa

AF:

0.203

Hom.:

5821

Bravo

AF:

0.167

Asia WGS

AF:

0.0870

AC:

305

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Timothy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2015

This alteration is classified as 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

-0.39

CADD

Benign

DANN

Benign

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over