rs216036

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000719.7(CACNA1C):c.3913-270A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,038 control chromosomes in the GnomAD database, including 6,844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6844 hom., cov: 32)

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.149

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 12-2648205-A-C is Benign according to our data. Variant chr12-2648205-A-C is described in ClinVar as Benign. ClinVar VariationId is 683271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3913-270A>C		intron_variant	Intron 30 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3913-270A>C		intron_variant	Intron 30 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3913-270A>C	intron_variant	Intron 30 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.4147-270A>C	intron_variant	Intron 32 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3913-270A>C	intron_variant	Intron 30 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.3913-3435A>C	intron_variant	Intron 30 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.4078-270A>C	intron_variant	Intron 31 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.4057-270A>C	intron_variant	Intron 32 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3913-270A>C	intron_variant	Intron 30 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3913-270A>C	intron_variant	Intron 30 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4003-270A>C	intron_variant	Intron 30 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.4003-270A>C	intron_variant	Intron 30 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.4003-270A>C	intron_variant	Intron 30 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.4003-270A>C	intron_variant	Intron 30 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.3997-270A>C	intron_variant	Intron 31 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3988-270A>C	intron_variant	Intron 31 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3973-270A>C	intron_variant	Intron 31 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.3997-3435A>C	intron_variant	Intron 31 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3988-3435A>C	intron_variant	Intron 31 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3913-3435A>C	intron_variant	Intron 30 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3913-3435A>C	intron_variant	Intron 30 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3907-3435A>C	intron_variant	Intron 30 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3913-270A>C	intron_variant	Intron 30 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3913-270A>C	intron_variant	Intron 30 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3904-270A>C	intron_variant	Intron 30 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.3913-3435A>C	intron_variant	Intron 30 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42255

AN:

151920

Hom.:

6827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.449

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.207

Gnomad SAS

AF:

0.286

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.278

AC:

42305

AN:

152038

Hom.:

6844

Cov.:

AF XY:

0.276

AC XY:

20524

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.449

AC:

18596

AN:

41408

American (AMR)

AF:

0.202

AC:

3088

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

864

AN:

3470

East Asian (EAS)

AF:

0.208

AC:

1073

AN:

5168

South Asian (SAS)

AF:

0.286

AC:

1376

AN:

4816

European-Finnish (FIN)

AF:

0.182

AC:

1933

AN:

10600

Middle Eastern (MID)

AF:

0.390

AC:

114

AN:

292

European-Non Finnish (NFE)

AF:

0.211

AC:

14333

AN:

67970

Other (OTH)

AF:

0.295

AC:

622

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1462

2924

4386

5848

7310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.267

Hom.:

941

Bravo

AF:

0.287

Asia WGS

AF:

0.260

AC:

902

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 19, 2018

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. -

Long QT syndrome

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.0

(source)

DANN

Benign

0.50

PhyloP100

-0.15

Mutation Taster

=100/0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over