rs1051375

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000719.7(CACNA1C):c.5361G>A(p.Thr1787=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,608,514 control chromosomes in the GnomAD database, including 398,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 28886 hom., cov: 34)

Exomes 𝑓: 0.71 ( 369370 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -3.82

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:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 12-2679713-G-A is Benign according to our data. Variant chr12-2679713-G-A is described in ClinVar as [Benign]. Clinvar id is 93413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2679713-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.82 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACNA1C	NM_000719.7 linkuse as main transcript	c.5361G>A	p.Thr1787=	synonymous_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.5361G>A	p.Thr1787=	synonymous_variant	42/47	ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1 linkuse as main transcript	n.334-1816C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.5361G>A	p.Thr1787=	synonymous_variant	42/47	5	NM_001167623.2	ENSP00000382512	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.5361G>A	p.Thr1787=	synonymous_variant	42/47	1	NM_000719.7	ENSP00000382563	Q13936-12
CACNA1C-AS1	ENST00000501371.5 linkuse as main transcript	n.295-1816C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.578

AC:

87834

AN:

152028

Hom.:

28877

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.613

Gnomad AMR

AF:

0.644

Gnomad ASJ

AF:

0.672

Gnomad EAS

AF:

0.624

Gnomad SAS

AF:

0.667

Gnomad FIN

AF:

0.767

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.726

Gnomad OTH

AF:

0.586

GnomAD3 exomes

AF:

0.677

AC:

160515

AN:

236924

Hom.:

55999

AF XY:

0.683

AC XY:

88041

AN XY:

128962

show subpopulations

Gnomad AFR exome

AF:

0.236

Gnomad AMR exome

AF:

0.706

Gnomad ASJ exome

AF:

0.664

Gnomad EAS exome

AF:

0.624

Gnomad SAS exome

AF:

0.665

Gnomad FIN exome

AF:

0.763

Gnomad NFE exome

AF:

0.723

Gnomad OTH exome

AF:

0.676

GnomAD4 exome

AF:

0.706

AC:

1028616

AN:

1456368

Hom.:

369370

Cov.:

AF XY:

0.706

AC XY:

511204

AN XY:

724000

show subpopulations

Gnomad4 AFR exome

AF:

0.211

Gnomad4 AMR exome

AF:

0.696

Gnomad4 ASJ exome

AF:

0.661

Gnomad4 EAS exome

AF:

0.598

Gnomad4 SAS exome

AF:

0.657

Gnomad4 FIN exome

AF:

0.758

Gnomad4 NFE exome

AF:

0.731

Gnomad4 OTH exome

AF:

0.671

GnomAD4 genome

AF:

0.577

AC:

87853

AN:

152146

Hom.:

28886

Cov.:

AF XY:

0.581

AC XY:

43218

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.236

Gnomad4 AMR

AF:

0.644

Gnomad4 ASJ

AF:

0.672

Gnomad4 EAS

AF:

0.623

Gnomad4 SAS

AF:

0.666

Gnomad4 FIN

AF:

0.767

Gnomad4 NFE

AF:

0.727

Gnomad4 OTH

AF:

0.589

Alfa

AF:

0.681

Hom.:

18547

Bravo

AF:

0.553

Asia WGS

AF:

0.637

AC:

2211

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Sep 04, 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

-0.86

CADD

Benign

0.0040

DANN

Benign

0.90

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