19-13286510-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001127222.2(CACNA1A):c.3546C>A(p.Val1182Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000821 in 1,217,950 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. V1182V) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.594

Publications

0 publications found

Variant links:

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

CACNA1A Gene-Disease associations (from GenCC):

episodic ataxia type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
developmental and epileptic encephalopathy, 42
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
migraine, familial hemiplegic, 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
benign paroxysmal torticollis of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial or sporadic hemiplegic migraine
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP7

Synonymous conserved (PhyloP=-0.594 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.3546C>A	p.Val1182Val	synonymous_variant	Exon 20 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.3546C>A	p.Val1182Val	synonymous_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.3558C>A	p.Val1186Val	synonymous_variant	Exon 20 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.3552C>A	p.Val1184Val	synonymous_variant	Exon 20 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.3408C>A	p.Val1136Val	synonymous_variant	Exon 19 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.3558C>A	p.Val1186Val	synonymous_variant	Exon 20 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.3552C>A	p.Val1184Val	synonymous_variant	Exon 20 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.3549C>A	p.Val1183Val	synonymous_variant	Exon 20 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.3549C>A		non_coding_transcript_exon_variant	Exon 20 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.3546C>A		non_coding_transcript_exon_variant	Exon 20 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.21e-7

AC:

AN:

1217950

Hom.:

Cov.:

AF XY:

0.00000166

AC XY:

AN XY:

603996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27252

American (AMR)

AF:

0.00

AC:

AN:

28704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18896

East Asian (EAS)

AF:

0.00

AC:

AN:

36930

South Asian (SAS)

AF:

0.00

AC:

AN:

65624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5018

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

935592

Other (OTH)

AF:

0.00

AC:

AN:

51228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.1

(source)

DANN

Benign

0.71

PhyloP100

-0.59

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