chr19-13312723-G-A

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.1614C>T(p.Tyr538Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,594,874 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 5 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0460

Publications

2 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:

ENSG00000306107 (HGNC:):

ENSG00000306107 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=-0.49).

BP6

Variant 19-13312723-G-A is Benign according to our data. Variant chr19-13312723-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.046 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00143 (218/152252) while in subpopulation NFE AF = 0.00265 (180/68016). AF 95% confidence interval is 0.00233. There are 0 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.1614C>T	p.Tyr538Tyr	synonymous_variant	Exon 12 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.1614C>T	p.Tyr538Tyr	synonymous_variant	Exon 12 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.1620C>T	p.Tyr540Tyr	synonymous_variant	Exon 12 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.1476C>T	p.Tyr492Tyr	synonymous_variant	Exon 11 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.1620C>T	p.Tyr540Tyr	synonymous_variant	Exon 12 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.1617C>T	p.Tyr539Tyr	synonymous_variant	Exon 12 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.1617C>T		non_coding_transcript_exon_variant	Exon 12 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.1614C>T		non_coding_transcript_exon_variant	Exon 12 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00265

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00162

AC:

375

AN:

232090

AF XY:

0.00156

show subpopulations

Gnomad AFR exome

AF:

0.000425

Gnomad AMR exome

AF:

0.000399

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000628

Gnomad FIN exome

AF:

0.000984

Gnomad NFE exome

AF:

0.00293

Gnomad OTH exome

AF:

0.000910

GnomAD4 exome

AF:

0.00253

AC:

3654

AN:

1442622

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

1762

AN XY:

717380

show subpopulations

African (AFR)

AF:

0.000407

AC:

AN:

31972

American (AMR)

AF:

0.000386

AC:

AN:

41398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25816

East Asian (EAS)

AF:

0.0000525

AC:

AN:

38080

South Asian (SAS)

AF:

0.000413

AC:

AN:

82414

European-Finnish (FIN)

AF:

0.00101

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00311

AC:

3429

AN:

1104306

Other (OTH)

AF:

0.00173

AC:

103

AN:

59670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

152

304

457

609

761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.00143

AC:

218

AN:

152252

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41528

American (AMR)

AF:

0.000523

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00265

AC:

180

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00201

Hom.:

Bravo

AF:

0.00133

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1A: BP4, BP7 -

Nov 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23397224) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

May 16, 2017

Eurofins Ntd Llc (ga)

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 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 28, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.9

(source)

DANN

Benign

0.51

PhyloP100

0.046

Mutation Taster

=89/11

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over