19-13231716-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001127222.2(CACNA1A):c.5394G>A(p.Ser1798Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000888 in 1,610,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000092 ( 1 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -5.87

Publications

1 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: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 19-13231716-C-T is Benign according to our data. Variant chr19-13231716-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 390293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.87 with no splicing effect.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.5394G>A	p.Ser1798Ser	synonymous_variant	Exon 35 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.5397G>A	p.Ser1799Ser	synonymous_variant	Exon 35 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.5394G>A	p.Ser1798Ser	synonymous_variant	Exon 35 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.5397G>A	p.Ser1799Ser	synonymous_variant	Exon 35 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.5412G>A	p.Ser1804Ser	synonymous_variant	Exon 36 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.5400G>A	p.Ser1800Ser	synonymous_variant	Exon 35 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.5397G>A	p.Ser1799Ser	synonymous_variant	Exon 35 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.5397G>A	p.Ser1799Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.5397G>A	p.Ser1799Ser	synonymous_variant	Exon 35 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.5256G>A	p.Ser1752Ser	synonymous_variant	Exon 34 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.5397G>A	p.Ser1799Ser	synonymous_variant	Exon 35 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.5412G>A	p.Ser1804Ser	synonymous_variant	Exon 36 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.5403G>A	p.Ser1801Ser	synonymous_variant	Exon 36 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.5400G>A	p.Ser1800Ser	synonymous_variant	Exon 35 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.5397G>A	p.Ser1799Ser	synonymous_variant	Exon 35 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.5397G>A	p.Ser1799Ser	synonymous_variant	Exon 35 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.5397G>A		non_coding_transcript_exon_variant	Exon 35 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*575G>A		non_coding_transcript_exon_variant	Exon 36 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1 link	n.*575G>A		3_prime_UTR_variant	Exon 36 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000536

AC:

AN:

242450

AF XY:

0.0000456

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000365

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000919

AC:

134

AN:

1457986

Hom.:

Cov.:

AF XY:

0.0000938

AC XY:

AN XY:

724946

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33406

American (AMR)

AF:

0.0000227

AC:

AN:

44022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39558

South Asian (SAS)

AF:

0.000257

AC:

AN:

85622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

1110118

Other (OTH)

AF:

0.000166

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.0000591

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

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:

0.0000772

Hom.:

Bravo

AF:

0.0000340

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1A: BP4, BP7 -

Aug 01, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 28, 2016

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.58

CADD

Benign

0.033

(source)

DANN

Benign

0.57

PhyloP100

-5.9

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