rs551355331

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000406454.8(CACNA1C):c.5477C>A(p.Thr1826Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,559,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

CACNA1C
ENST00000406454.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: -0.0620

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04078877).

BP6

Variant 12-2680395-C-A is Benign according to our data. Variant chr12-2680395-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191426.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5444+599C>A		intron_variant	Intron 42 of 46	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5444+599C>A		intron_variant	Intron 42 of 46	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000406454.8 link	c.5477C>A	p.Thr1826Asn	missense_variant	Exon 43 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.5444C>A	p.Thr1815Asn	missense_variant	Exon 42 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000399603.6 link	c.5444+599C>A		intron_variant	Intron 42 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5444+599C>A		intron_variant	Intron 42 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.5678+599C>A		intron_variant	Intron 44 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000683824.1 link	c.5609+599C>A		intron_variant	Intron 43 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.5588+599C>A		intron_variant	Intron 44 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.5567+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.5444+599C>A		intron_variant	Intron 42 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.5444+599C>A		intron_variant	Intron 42 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.5534+599C>A		intron_variant	Intron 42 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.5534+599C>A		intron_variant	Intron 42 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.5534+599C>A		intron_variant	Intron 42 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.5534+599C>A		intron_variant	Intron 42 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.5528+599C>A		intron_variant	Intron 43 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5519+599C>A		intron_variant	Intron 43 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5504+599C>A		intron_variant	Intron 43 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5501+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5501+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5501+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5495+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5486+599C>A		intron_variant	Intron 42 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5468+599C>A		intron_variant	Intron 41 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5468+599C>A		intron_variant	Intron 41 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5462+599C>A		intron_variant	Intron 41 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5444+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5444+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5444+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5444+599C>A		intron_variant	Intron 42 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5444+599C>A		intron_variant	Intron 42 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5435+599C>A		intron_variant	Intron 42 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5411+599C>A		intron_variant	Intron 41 of 45			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000175

AC:

AN:

165460

AF XY:

0.000204

show subpopulations

Gnomad AFR exome

AF:

0.000108

Gnomad AMR exome

AF:

0.000230

Gnomad ASJ exome

AF:

0.000116

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000307

Gnomad OTH exome

AF:

0.000217

GnomAD4 exome

AF:

0.000196

AC:

276

AN:

1406954

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

146

AN XY:

694776

show subpopulations

African (AFR)

AF:

0.0000311

AC:

AN:

32180

American (AMR)

AF:

0.000270

AC:

AN:

37036

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25226

East Asian (EAS)

AF:

0.00

AC:

AN:

36680

South Asian (SAS)

AF:

0.00

AC:

AN:

79764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49076

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000227

AC:

246

AN:

1082932

Other (OTH)

AF:

0.000291

AC:

AN:

58362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000158

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41568

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68018

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000131

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000112

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published in association with CACNA1C-related disorders to our knowledge; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 25650408) -

not specified

Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.2

(source)

DANN

Benign

0.62

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.022

M_CAP

Benign

0.057

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-0.37

PhyloP100

-0.062

PROVEAN

Benign

-0.19

N;N

REVEL

Benign

0.18

Sift

Benign

0.35

T;T

Sift4G

Benign

0.49

T;T

Polyphen

0.0010

.;B

Vest4

0.085

MVP

0.50

ClinPred

0.0036

GERP RS

-0.59

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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