rs184684058

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000719.7(CACNA1C):c.2766G>A(p.Pro922Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,612,976 control chromosomes in the GnomAD database, including 2 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 0.00049 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -6.76

Publications

1 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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 12-2595976-G-A is Benign according to our data. Variant chr12-2595976-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195467.

BP7

Synonymous conserved (PhyloP=-6.76 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000493 (75/152170) while in subpopulation AFR AF = 0.00169 (70/41532). AF 95% confidence interval is 0.00137. There are 2 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2856G>A	p.Pro952Pro	synonymous_variant	Exon 20 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2931G>A	p.Pro977Pro	synonymous_variant	Exon 21 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2856G>A	p.Pro952Pro	synonymous_variant	Exon 20 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2856G>A	p.Pro952Pro	synonymous_variant	Exon 20 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2856G>A	p.Pro952Pro	synonymous_variant	Exon 20 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2856G>A	p.Pro952Pro	synonymous_variant	Exon 20 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2841G>A	p.Pro947Pro	synonymous_variant	Exon 21 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2841G>A	p.Pro947Pro	synonymous_variant	Exon 21 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2757G>A	p.Pro919Pro	synonymous_variant	Exon 20 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2766G>A	p.Pro922Pro	synonymous_variant	Exon 20 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1373G>A		non_coding_transcript_exon_variant	Exon 18 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1373G>A		3_prime_UTR_variant	Exon 18 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000205

AC:

AN:

248640

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1460806

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

726680

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

33454

American (AMR)

AF:

0.000425

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53146

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000747

AC:

AN:

1111464

Other (OTH)

AF:

0.000116

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000493

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

41532

American (AMR)

AF:

0.000196

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.000334

Hom.:

Bravo

AF:

0.000514

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 06, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.77

CADD

Benign

1.6

(source)

DANN

Benign

0.67

PhyloP100

-6.8

Mutation Taster

=78/22

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