rs202227691

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000719.7(CACNA1C):c.1872G>A(p.Leu624Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,609,748 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L624L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.82

Publications

0 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 12-2567771-G-A is Benign according to our data. Variant chr12-2567771-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 456947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.82 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000105 (16/152318) while in subpopulation AMR AF = 0.000588 (9/15306). AF 95% confidence interval is 0.000306. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1962G>A	p.Leu654Leu	synonymous_variant	Exon 13 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2037G>A	p.Leu679Leu	synonymous_variant	Exon 14 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1962G>A	p.Leu654Leu	synonymous_variant	Exon 13 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1962G>A	p.Leu654Leu	synonymous_variant	Exon 13 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1962G>A	p.Leu654Leu	synonymous_variant	Exon 13 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1962G>A	p.Leu654Leu	synonymous_variant	Exon 13 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1947G>A	p.Leu649Leu	synonymous_variant	Exon 14 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1947G>A	p.Leu649Leu	synonymous_variant	Exon 14 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1863G>A	p.Leu621Leu	synonymous_variant	Exon 13 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1872G>A	p.Leu624Leu	synonymous_variant	Exon 13 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*479G>A		non_coding_transcript_exon_variant	Exon 11 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*479G>A		3_prime_UTR_variant	Exon 11 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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

GnomAD2 exomes

AF:

0.0000364

AC:

AN:

247096

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.000326

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1457430

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725054

show subpopulations

African (AFR)

AF:

0.000599

AC:

AN:

33392

American (AMR)

AF:

0.000112

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

85910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108356

Other (OTH)

AF:

0.0000498

AC:

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.000105

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41564

American (AMR)

AF:

0.000588

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00

Hom.:

Bravo

AF:

0.0000907

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CACNA1C-related disorder

Benign:1

Jun 25, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Long QT syndrome

Benign:1

Dec 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 30, 2019

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

-0.70

CADD

Benign

0.31

(source)

DANN

Benign

0.61

PhyloP100

-1.8

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