rs376124689

Positions:

chr12-2679743-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000719.7(CACNA1C):c.5391C>G(p.Pro1797Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,600,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0290

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:):

CACNA1C-AS1 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 12-2679743-C-G is Benign according to our data. Variant chr12-2679743-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 238175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.029 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000519 (79/152342) while in subpopulation AFR AF= 0.00185 (77/41594). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.5625C>G	p.Pro1875Pro	synonymous_variant	44/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.5358C>G	p.Pro1786Pro	synonymous_variant	41/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.5556C>G	p.Pro1852Pro	synonymous_variant	43/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.5535C>G	p.Pro1845Pro	synonymous_variant	44/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.5514C>G	p.Pro1838Pro	synonymous_variant	42/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.5481C>G	p.Pro1827Pro	synonymous_variant	42/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.5481C>G	p.Pro1827Pro	synonymous_variant	42/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.5481C>G	p.Pro1827Pro	synonymous_variant	42/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.5481C>G	p.Pro1827Pro	synonymous_variant	42/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.5475C>G	p.Pro1825Pro	synonymous_variant	43/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5466C>G	p.Pro1822Pro	synonymous_variant	43/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5451C>G	p.Pro1817Pro	synonymous_variant	43/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5448C>G	p.Pro1816Pro	synonymous_variant	42/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5448C>G	p.Pro1816Pro	synonymous_variant	42/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5448C>G	p.Pro1816Pro	synonymous_variant	42/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5442C>G	p.Pro1814Pro	synonymous_variant	42/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5433C>G	p.Pro1811Pro	synonymous_variant	42/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5415C>G	p.Pro1805Pro	synonymous_variant	41/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5415C>G	p.Pro1805Pro	synonymous_variant	41/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5409C>G	p.Pro1803Pro	synonymous_variant	41/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5391C>G	p.Pro1797Pro	synonymous_variant	42/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5382C>G	p.Pro1794Pro	synonymous_variant	42/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5358C>G	p.Pro1786Pro	synonymous_variant	41/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

222362

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

120902

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.0000628

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000442

AC:

AN:

1448132

Hom.:

Cov.:

AF XY:

0.0000445

AC XY:

AN XY:

718866

show subpopulations

Gnomad4 AFR exome

AF:

0.00157

Gnomad4 AMR exome

AF:

0.0000701

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.000519

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000641

Hom.:

Bravo

AF:

0.000536

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	CACNA1C: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2025

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2016

This alteration is classified as likely 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

-0.44

CADD

Benign

5.3

DANN

Benign

0.77

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