12-2593229-G-A

Position:

chr12-2593229-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):c.2547G>A(p.Glu849Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,588 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.484

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

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

BP6

Variant 12-2593229-G-A is Benign according to our data. Variant chr12-2593229-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 527070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.484 with no splicing effect.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 linkuse as main transcript	c.2637G>A	p.Glu879Glu	synonymous_variant	19/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 linkuse as main transcript	c.2712G>A	p.Glu904Glu	synonymous_variant	20/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 linkuse as main transcript	c.2637G>A	p.Glu879Glu	synonymous_variant	19/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 linkuse as main transcript	c.2637G>A	p.Glu879Glu	synonymous_variant	19/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 linkuse as main transcript	c.2637G>A	p.Glu879Glu	synonymous_variant	19/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 linkuse as main transcript	c.2637G>A	p.Glu879Glu	synonymous_variant	19/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 linkuse as main transcript	c.2622G>A	p.Glu874Glu	synonymous_variant	20/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 linkuse as main transcript	c.2622G>A	p.Glu874Glu	synonymous_variant	20/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 linkuse as main transcript	c.2538G>A	p.Glu846Glu	synonymous_variant	19/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 linkuse as main transcript	c.2547G>A	p.Glu849Glu	synonymous_variant	19/46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 linkuse as main transcript	n.*1154G>A		non_coding_transcript_exon_variant	17/27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 linkuse as main transcript	n.*1154G>A		3_prime_UTR_variant	17/27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000478

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248576

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461362

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.000478

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2020

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

-0.39

CADD

Benign

6.7

DANN

Benign

0.53

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