rs202194703

Positions:

chr12-2668950-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_000719.7(CACNA1C):c.4641C>T(p.Asn1547Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,972 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.71

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-AS2 (HGNC:):

CACNA1C-AS2 links:

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

CACNA1C-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23).

BP6

Variant 12-2668950-C-T is Benign according to our data. Variant chr12-2668950-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93408.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BP7

Synonymous conserved (PhyloP=1.71 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000302 (46/152320) while in subpopulation AMR AF= 0.000849 (13/15306). AF 95% confidence interval is 0.00058. There are 1 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.4875C>T	p.Asn1625Asn	synonymous_variant	40/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.4608C>T	p.Asn1536Asn	synonymous_variant	37/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.4806C>T	p.Asn1602Asn	synonymous_variant	39/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.4785C>T	p.Asn1595Asn	synonymous_variant	40/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.4707C>T	p.Asn1569Asn	synonymous_variant	38/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.4731C>T	p.Asn1577Asn	synonymous_variant	38/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.4731C>T	p.Asn1577Asn	synonymous_variant	38/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.4731C>T	p.Asn1577Asn	synonymous_variant	38/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.4731C>T	p.Asn1577Asn	synonymous_variant	38/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.4725C>T	p.Asn1575Asn	synonymous_variant	39/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.4716C>T	p.Asn1572Asn	synonymous_variant	39/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.4701C>T	p.Asn1567Asn	synonymous_variant	39/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.4692C>T	p.Asn1564Asn	synonymous_variant	38/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.4683C>T	p.Asn1561Asn	synonymous_variant	38/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.4608C>T	p.Asn1536Asn	synonymous_variant	37/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.4608C>T	p.Asn1536Asn	synonymous_variant	37/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.4602C>T	p.Asn1534Asn	synonymous_variant	37/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.4641C>T	p.Asn1547Asn	synonymous_variant	38/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.4632C>T	p.Asn1544Asn	synonymous_variant	38/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.4608C>T	p.Asn1536Asn	synonymous_variant	37/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

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:

0.0000598

AC:

AN:

250672

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.000693

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000302

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.000849

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:

0.0000986

Hom.:

Bravo

AF:

0.000261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 02, 2013

- -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2019

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

-0.23

CADD

Benign

DANN

Benign

0.88

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