12-2493224-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_000719.7(CACNA1C):c.951G>T(p.Ala317Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A317A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.641

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP7

Synonymous conserved (PhyloP=-0.641 with no splicing effect.

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1041G>T	p.Ala347Ala	synonymous_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1041G>T	p.Ala347Ala	synonymous_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1041G>T	p.Ala347Ala	synonymous_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1041G>T	p.Ala347Ala	synonymous_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1041G>T	p.Ala347Ala	synonymous_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1041G>T	p.Ala347Ala	synonymous_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.942G>T	p.Ala314Ala	synonymous_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.951G>T	p.Ala317Ala	synonymous_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.888G>T	p.Ala296Ala	synonymous_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.951G>T		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000402

AC:

AN:

248734

AF XY:

0.0000370

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:

0.000464

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111810

Other (OTH)

AF:

0.0000166

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68052

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.9

(source)

DANN

Benign

0.61

PhyloP100

-0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over