rs137904817

Positions:

chr12-2677087-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.4829-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,611,758 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.59

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-2677087-G-A is Benign according to our data. Variant chr12-2677087-G-A is described in ClinVar as [Benign]. Clinvar id is 136629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2677087-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00178 (271/151988) while in subpopulation AFR AF= 0.00632 (262/41454). AF 95% confidence interval is 0.00569. There are 3 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 271 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
CACNA1C	NM_000719.7 linkuse as main transcript	c.4829-7G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.4829-7G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1 linkuse as main transcript	n.1144C>T	non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.4829-7G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001167623.2	ENSP00000382512	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.4829-7G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000719.7	ENSP00000382563	Q13936-12
CACNA1C-AS1	ENST00000501371.5 linkuse as main transcript	n.1105C>T	non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

270

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00631

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000433

AC:

107

AN:

247018

Hom.:

AF XY:

0.000358

AC XY:

AN XY:

133906

show subpopulations

Gnomad AFR exome

AF:

0.00663

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000164

AC:

240

AN:

1459770

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

725958

show subpopulations

Gnomad4 AFR exome

AF:

0.00622

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.00178

AC:

271

AN:

151988

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00632

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.000818

Hom.:

Bravo

AF:

0.00173

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2013	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

CACNA1C: BP4, BS1, BS2 -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.33

DANN

Benign

0.89

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