chr19-13214600-C-T

Position:

chr19-13214600-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_001127222.2(CACNA1A):c.5740G>A(p.Asp1914Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,212 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. D1914D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.06

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 links:

CACNA1A (HGNC:):

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.34954685).

BP6

Variant 19-13214600-C-T is Benign according to our data. Variant chr19-13214600-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 585577.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.5740G>A	p.Asp1914Asn	missense_variant	39/47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.5740G>A	p.Asp1914Asn	missense_variant	39/47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 linkuse as main transcript	c.5758G>A	p.Asp1920Asn	missense_variant	40/48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 linkuse as main transcript	c.5746G>A	p.Asp1916Asn	missense_variant	39/47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	39/47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	39/47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	39/46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 linkuse as main transcript	c.5602G>A	p.Asp1868Asn	missense_variant	38/46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	39/47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 linkuse as main transcript	c.5758G>A	p.Asp1920Asn	missense_variant	40/48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 linkuse as main transcript	c.5749G>A	p.Asp1917Asn	missense_variant	40/48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 linkuse as main transcript	c.5746G>A	p.Asp1916Asn	missense_variant	39/47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	39/47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	39/47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 linkuse as main transcript	c.5743G>A	p.Asp1915Asn	missense_variant	39/46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.1 linkuse as main transcript	n.*42G>A		non_coding_transcript_exon_variant	4/10	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000636768.1 linkuse as main transcript	n.*42G>A		3_prime_UTR_variant	4/10	5		ENSP00000490190.2	A0A1B0GUP3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247780

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134468

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1460986

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726714

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 23, 2022

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.064

.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.35

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.77

.;.;.;.;N;.;.;.;.;.;.;.;.;.;N;.;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.22

Sift

Uncertain

0.0080

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.013

D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.49

MVP

0.81

MPC

2.2

ClinPred

0.53

GERP RS

4.7

Varity_R

0.21

gMVP

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over