12-2372770-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000719.7(CACNA1C):c.478-76206T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 152,136 control chromosomes in the GnomAD database, including 59,898 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.88 ( 59898 hom., cov: 35)

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.247

Publications

6 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.478-76206T>C		intron_variant	Intron 3 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.478-76206T>C		intron_variant	Intron 3 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.478-76206T>C	intron_variant	Intron 3 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.568-76206T>C	intron_variant	Intron 3 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.478-76206T>C	intron_variant	Intron 3 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.478-76206T>C	intron_variant	Intron 3 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.568-76206T>C	intron_variant	Intron 3 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.478-76206T>C	intron_variant	Intron 3 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.478-76206T>C	intron_variant	Intron 3 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.478-76206T>C	intron_variant	Intron 3 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.568-76206T>C	intron_variant	Intron 3 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.568-76206T>C	intron_variant	Intron 3 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.568-76206T>C	intron_variant	Intron 3 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.568-76206T>C	intron_variant	Intron 3 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.478-76206T>C	intron_variant	Intron 3 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.478-76206T>C	intron_variant	Intron 3 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.478-76206T>C	intron_variant	Intron 3 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.478-76206T>C	intron_variant	Intron 3 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.478-76206T>C	intron_variant	Intron 3 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.478-76206T>C	intron_variant	Intron 3 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.478-76206T>C	intron_variant	Intron 3 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.478-76206T>C	intron_variant	Intron 3 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.478-76206T>C	intron_variant	Intron 3 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.478-76206T>C	intron_variant	Intron 3 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.478-76206T>C	intron_variant	Intron 3 of 45			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.427-76206T>C	intron_variant	Intron 2 of 5			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.478-76206T>C	intron_variant	Intron 3 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.885

AC:

134464

AN:

152018

Hom.:

59825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.968

Gnomad AMI

AF:

0.803

Gnomad AMR

AF:

0.901

Gnomad ASJ

AF:

0.881

Gnomad EAS

AF:

0.727

Gnomad SAS

AF:

0.823

Gnomad FIN

AF:

0.774

Gnomad MID

AF:

0.866

Gnomad NFE

AF:

0.865

Gnomad OTH

AF:

0.887

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

GnomAD4 genome

AF:

0.885

AC:

134597

AN:

152136

Hom.:

59898

Cov.:

AF XY:

0.879

AC XY:

65314

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.968

AC:

40255

AN:

41578

American (AMR)

AF:

0.901

AC:

13790

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.881

AC:

3054

AN:

3468

East Asian (EAS)

AF:

0.727

AC:

3751

AN:

5160

South Asian (SAS)

AF:

0.823

AC:

3975

AN:

4830

European-Finnish (FIN)

AF:

0.774

AC:

8162

AN:

10546

Middle Eastern (MID)

AF:

0.870

AC:

254

AN:

292

European-Non Finnish (NFE)

AF:

0.865

AC:

58751

AN:

67940

Other (OTH)

AF:

0.890

AC:

1876

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

800

1601

2401

3202

4002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.873

Hom.:

170960

Bravo

AF:

0.897

Asia WGS

AF:

0.790

AC:

2749

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

1.4

(source)

DANN

Benign

0.62

PhyloP100

-0.25

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

Computational scores

Splicing

Publications

Other links and lift over