rs778991232

Variant names:

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.3363G>A(p.Leu1121Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,608,722 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 1 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.831

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 12-2608517-G-A is Benign according to our data. Variant chr12-2608517-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 527062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.831 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000515 (75/1456520) while in subpopulation SAS AF = 0.000821 (70/85246). AF 95% confidence interval is 0.000666. There are 1 homozygotes in GnomAdExome4. There are 53 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.3513G>A	p.Leu1171Leu	synonymous_variant	Exon 28 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.3528G>A	p.Leu1176Leu	synonymous_variant	Exon 28 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.3423G>A	p.Leu1141Leu	synonymous_variant	Exon 28 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.3453G>A	p.Leu1151Leu	synonymous_variant	Exon 27 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.3453G>A	p.Leu1151Leu	synonymous_variant	Exon 27 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.3453G>A	p.Leu1151Leu	synonymous_variant	Exon 27 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.3453G>A	p.Leu1151Leu	synonymous_variant	Exon 27 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3438G>A	p.Leu1146Leu	synonymous_variant	Exon 28 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3423G>A	p.Leu1141Leu	synonymous_variant	Exon 28 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3438G>A	p.Leu1146Leu	synonymous_variant	Exon 28 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3354G>A	p.Leu1118Leu	synonymous_variant	Exon 27 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.3363G>A	p.Leu1121Leu	synonymous_variant	Exon 27 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1970G>A		non_coding_transcript_exon_variant	Exon 25 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1970G>A		3_prime_UTR_variant	Exon 25 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

242420

AF XY:

0.000160

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000515

AC:

AN:

1456520

Hom.:

Cov.:

AF XY:

0.0000732

AC XY:

AN XY:

723996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

43982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.000821

AC:

AN:

85246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109240

Other (OTH)

AF:

0.0000332

AC:

AN:

60232

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:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.00000378

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

Sep 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 11, 2021

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

-0.53

CADD

Benign

8.9

(source)

DANN

Benign

0.80

PhyloP100

0.83

Mutation Taster

=95/5

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