chr19-13212693-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001127222.2(CACNA1A):c.5988G>A(p.Thr1996Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000358 in 1,508,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1996T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.78

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:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

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

BP6

Variant 19-13212693-C-T is Benign according to our data. Variant chr19-13212693-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.78 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000391 (53/1356676) while in subpopulation EAS AF = 0.000834 (32/38380). AF 95% confidence interval is 0.000606. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.5988G>A	p.Thr1996Thr	synonymous_variant	Exon 41 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.5991G>A	p.Thr1997Thr	synonymous_variant	Exon 41 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.5988G>A	p.Thr1996Thr	synonymous_variant	Exon 41 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.5991G>A	p.Thr1997Thr	synonymous_variant	Exon 41 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.6006G>A	p.Thr2002Thr	synonymous_variant	Exon 42 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.5994G>A	p.Thr1998Thr	synonymous_variant	Exon 41 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.5991G>A	p.Thr1997Thr	synonymous_variant	Exon 41 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.5991G>A	p.Thr1997Thr	synonymous_variant	Exon 41 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.5991G>A	p.Thr1997Thr	synonymous_variant	Exon 41 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.5850G>A	p.Thr1950Thr	synonymous_variant	Exon 40 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.5991G>A	p.Thr1997Thr	synonymous_variant	Exon 41 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.6006G>A	p.Thr2002Thr	synonymous_variant	Exon 42 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.5997G>A	p.Thr1999Thr	synonymous_variant	Exon 42 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.5994G>A	p.Thr1998Thr	synonymous_variant	Exon 41 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.5991G>A	p.Thr1997Thr	synonymous_variant	Exon 41 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.5991G>A	p.Thr1997Thr	synonymous_variant	Exon 41 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.*290G>A		non_coding_transcript_exon_variant	Exon 40 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*1203G>A		non_coding_transcript_exon_variant	Exon 42 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2 link	n.*290G>A		3_prime_UTR_variant	Exon 40 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*1203G>A		3_prime_UTR_variant	Exon 42 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151924

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000740

AC:

AN:

162232

AF XY:

0.0000816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000748

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1356676

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

663320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30120

American (AMR)

AF:

0.00

AC:

AN:

28508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19634

East Asian (EAS)

AF:

0.000834

AC:

AN:

38380

South Asian (SAS)

AF:

0.00

AC:

AN:

68802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4754

European-Non Finnish (NFE)

AF:

0.0000179

AC:

AN:

1061522

Other (OTH)

AF:

0.0000359

AC:

AN:

55698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2114

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 21, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 28, 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

1.8

(source)

DANN

Benign

0.53

PhyloP100

-3.8

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

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over