NM_000719.7:c.1419C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):c.1419C>T(p.Ser473Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,606,938 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 (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.85

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 12-2549971-C-T is Benign according to our data. Variant chr12-2549971-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.85 with no splicing effect.

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.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1509C>T	p.Ser503Ser	synonymous_variant	Exon 10 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1584C>T	p.Ser528Ser	synonymous_variant	Exon 11 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1509C>T	p.Ser503Ser	synonymous_variant	Exon 10 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1509C>T	p.Ser503Ser	synonymous_variant	Exon 10 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1509C>T	p.Ser503Ser	synonymous_variant	Exon 10 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1509C>T	p.Ser503Ser	synonymous_variant	Exon 10 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1494C>T	p.Ser498Ser	synonymous_variant	Exon 11 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1494C>T	p.Ser498Ser	synonymous_variant	Exon 11 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1410C>T	p.Ser470Ser	synonymous_variant	Exon 10 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1419C>T	p.Ser473Ser	synonymous_variant	Exon 10 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*26C>T		non_coding_transcript_exon_variant	Exon 8 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*26C>T		3_prime_UTR_variant	Exon 8 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000182

AC:

AN:

236824

AF XY:

0.000187

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000447

Gnomad NFE exome

AF:

0.000289

Gnomad OTH exome

AF:

0.000345

GnomAD4 exome

AF:

0.000232

AC:

337

AN:

1454758

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

165

AN XY:

722810

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33364

American (AMR)

AF:

0.00

AC:

AN:

43896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39418

South Asian (SAS)

AF:

0.00

AC:

AN:

84456

European-Finnish (FIN)

AF:

0.000397

AC:

AN:

52914

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000277

AC:

307

AN:

1108786

Other (OTH)

AF:

0.0000997

AC:

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

152180

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000147

Hom.:

Bravo

AF:

0.000102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 16, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1C: BP4, BP7 -

not specified

Benign:1

Oct 30, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1C-related disorder

Benign:1

Feb 23, 2024

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). -

Long QT syndrome

Benign:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 27, 2018

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

-0.52

CADD

Benign

5.9

(source)

DANN

Benign

0.87

PhyloP100

-1.9

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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