rs137904817

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.4829-7G>A variant causes a splice region, 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, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.59

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 links:

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

ITFG2-AS1 links:

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

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 136629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 271 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4829-7G>A		splice_region_variant, intron_variant	Intron 39 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.4829-7G>A		splice_region_variant, intron_variant	Intron 39 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.5063-7G>A	splice_region_variant, intron_variant	Intron 41 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.4796-7G>A	splice_region_variant, intron_variant	Intron 38 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.4994-7G>A	splice_region_variant, intron_variant	Intron 40 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.4973-7G>A	splice_region_variant, intron_variant	Intron 41 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.4952-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4919-7G>A	splice_region_variant, intron_variant	Intron 39 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.4919-7G>A	splice_region_variant, intron_variant	Intron 39 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.4919-7G>A	splice_region_variant, intron_variant	Intron 39 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.4919-7G>A	splice_region_variant, intron_variant	Intron 39 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.4913-7G>A	splice_region_variant, intron_variant	Intron 40 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.4904-7G>A	splice_region_variant, intron_variant	Intron 40 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.4889-7G>A	splice_region_variant, intron_variant	Intron 40 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.4886-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.4886-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.4886-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.4880-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.4871-7G>A	splice_region_variant, intron_variant	Intron 39 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.4853-7G>A	splice_region_variant, intron_variant	Intron 38 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.4853-7G>A	splice_region_variant, intron_variant	Intron 38 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.4847-7G>A	splice_region_variant, intron_variant	Intron 38 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.4829-7G>A	splice_region_variant, intron_variant	Intron 39 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.4820-7G>A	splice_region_variant, intron_variant	Intron 39 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.4796-7G>A	splice_region_variant, intron_variant	Intron 38 of 45			ENSP00000507309.1

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

GnomAD2 exomes

AF:

0.000433

AC:

107

AN:

247018

AF XY:

0.000358

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 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

African (AFR)

AF:

0.00622

AC:

208

AN:

33440

American (AMR)

AF:

0.000179

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110976

Other (OTH)

AF:

0.000249

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00178

AC:

271

AN:

151988

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00632

AC:

262

AN:

41454

American (AMR)

AF:

0.000196

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.00191

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000818

Hom.:

Bravo

AF:

0.00173

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Oct 06, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1C: BP4, BS1, BS2

Sep 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Long QT syndrome

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.33

(source)

DANN

Benign

0.89

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism

(source)

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over