19-13286525-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001127222.2(CACNA1A):c.3531C>A(p.Pro1177Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,492,082 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1177P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.436

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 19-13286525-G-T is Benign according to our data. Variant chr19-13286525-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283514.

BP7

Synonymous conserved (PhyloP=0.436 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000664 (101/152090) while in subpopulation AFR AF = 0.00214 (89/41494). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.3531C>A	p.Pro1177Pro	synonymous_variant	Exon 20 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.3534C>A	p.Pro1178Pro	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.3531C>A	p.Pro1177Pro	synonymous_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.3534C>A	p.Pro1178Pro	synonymous_variant	Exon 20 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.3543C>A	p.Pro1181Pro	synonymous_variant	Exon 20 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.3537C>A	p.Pro1179Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.3534C>A	p.Pro1178Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.3534C>A	p.Pro1178Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.3534C>A	p.Pro1178Pro	synonymous_variant	Exon 20 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.3393C>A	p.Pro1131Pro	synonymous_variant	Exon 19 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.3534C>A	p.Pro1178Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.3543C>A	p.Pro1181Pro	synonymous_variant	Exon 20 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.3534C>A	p.Pro1178Pro	synonymous_variant	Exon 20 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.3537C>A	p.Pro1179Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.3534C>A	p.Pro1178Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.3534C>A	p.Pro1178Pro	synonymous_variant	Exon 20 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.3534C>A		non_coding_transcript_exon_variant	Exon 20 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.3531C>A		non_coding_transcript_exon_variant	Exon 20 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.000665

AC:

101

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000244

AC:

AN:

172470

AF XY:

0.000186

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000274

Gnomad EAS exome

AF:

0.000805

Gnomad FIN exome

AF:

0.0000601

Gnomad NFE exome

AF:

0.0000479

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000208

AC:

279

AN:

1339992

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

133

AN XY:

660114

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

29694

American (AMR)

AF:

0.00

AC:

AN:

30080

Ashkenazi Jewish (ASJ)

AF:

0.000449

AC:

AN:

20040

East Asian (EAS)

AF:

0.00450

AC:

174

AN:

38678

South Asian (SAS)

AF:

0.0000574

AC:

AN:

69726

European-Finnish (FIN)

AF:

0.0000201

AC:

AN:

49800

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5264

European-Non Finnish (NFE)

AF:

0.0000106

AC:

AN:

1041376

Other (OTH)

AF:

0.000163

AC:

AN:

55334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.000664

AC:

101

AN:

152090

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41494

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00175

AC:

AN:

5154

South Asian (SAS)

AF:

0.000208

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

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:

0.000435

Hom.:

Bravo

AF:

0.000975

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 09, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 27, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Nov 29, 2016

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 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Feb 23, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

-0.57

CADD

Benign

3.3

(source)

DANN

Benign

0.69

PhyloP100

0.44

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