rs216008

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000719.7(CACNA1C):c.3786C>T(p.Phe1262Phe) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,611,566 control chromosomes in the GnomAD database, including 32,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3524 hom., cov: 31)

Exomes 𝑓: 0.19 ( 28895 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.91

Publications

34 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 12-2611971-C-T is Benign according to our data. Variant chr12-2611971-C-T is described in ClinVar as Benign. ClinVar VariationId is 93404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.3936C>T	p.Phe1312Phe	synonymous_variant	Exon 30 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.3951C>T	p.Phe1317Phe	synonymous_variant	Exon 30 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.3846C>T	p.Phe1282Phe	synonymous_variant	Exon 30 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.3876C>T	p.Phe1292Phe	synonymous_variant	Exon 29 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.3876C>T	p.Phe1292Phe	synonymous_variant	Exon 29 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.3876C>T	p.Phe1292Phe	synonymous_variant	Exon 29 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.3876C>T	p.Phe1292Phe	synonymous_variant	Exon 29 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.3861C>T	p.Phe1287Phe	synonymous_variant	Exon 30 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.3846C>T	p.Phe1282Phe	synonymous_variant	Exon 30 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.3861C>T	p.Phe1287Phe	synonymous_variant	Exon 30 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.3777C>T	p.Phe1259Phe	synonymous_variant	Exon 29 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.3786C>T	p.Phe1262Phe	synonymous_variant	Exon 29 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*2393C>T		non_coding_transcript_exon_variant	Exon 27 of 27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.*2393C>T		3_prime_UTR_variant	Exon 27 of 27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31964

AN:

151950

Hom.:

3522

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.226

Gnomad ASJ

AF:

0.233

Gnomad EAS

AF:

0.365

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.162

Gnomad MID

AF:

0.280

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.228

GnomAD2 exomes

AF:

0.210

AC:

52496

AN:

249972

AF XY:

0.210

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.233

Gnomad EAS exome

AF:

0.351

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.184

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.194

AC:

282850

AN:

1459498

Hom.:

28895

Cov.:

AF XY:

0.195

AC XY:

141676

AN XY:

726220

show subpopulations

African (AFR)

AF:

0.236

AC:

7874

AN:

33416

American (AMR)

AF:

0.221

AC:

9856

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

6225

AN:

26092

East Asian (EAS)

AF:

0.378

AC:

14989

AN:

39668

South Asian (SAS)

AF:

0.234

AC:

20151

AN:

86146

European-Finnish (FIN)

AF:

0.161

AC:

8568

AN:

53382

Middle Eastern (MID)

AF:

0.269

AC:

1547

AN:

5758

European-Non Finnish (NFE)

AF:

0.181

AC:

201250

AN:

1110030

Other (OTH)

AF:

0.205

AC:

12390

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

10400

20800

31200

41600

52000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7226

14452

21678

28904

36130

<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:

0.210

AC:

31978

AN:

152068

Hom.:

3524

Cov.:

AF XY:

0.212

AC XY:

15766

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.233

AC:

9666

AN:

41472

American (AMR)

AF:

0.226

AC:

3447

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

807

AN:

3470

East Asian (EAS)

AF:

0.364

AC:

1877

AN:

5152

South Asian (SAS)

AF:

0.239

AC:

1151

AN:

4808

European-Finnish (FIN)

AF:

0.162

AC:

1720

AN:

10596

Middle Eastern (MID)

AF:

0.264

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.186

AC:

12672

AN:

67986

Other (OTH)

AF:

0.224

AC:

472

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1271

2542

3812

5083

6354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.194

Hom.:

3022

Bravo

AF:

0.212

Asia WGS

AF:

0.255

AC:

889

AN:

3478

EpiCase

AF:

0.195

EpiControl

AF:

0.196

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 13, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Timothy syndrome

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 18, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

-0.30

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

7.9

Mutation Taster

=28/72

polymorphism (auto)

(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