chr19-13506163-G-A

Position:

• chr19-13506163-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):​c.62C>T​(p.Ala21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,546,916 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.76

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 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=0.0070285797).
• BP6: Variant 19-13506163-G-A is Benign according to our data. Variant chr19-13506163-G-A is described in ClinVar as [Benign]. Clinvar id is 385048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000368 (56/152228) while in subpopulation EAS AF= 0.0105 (54/5148). AF 95% confidence interval is 0.00826. There are 1 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.62C>T	p.Ala21Val	missense_variant	1/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.62C>T	p.Ala21Val	missense_variant	1/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.62C>T	p.Ala21Val	missense_variant	1/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.62C>T	p.Ala21Val	missense_variant	1/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.62C>T	p.Ala21Val	missense_variant	1/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.62C>T	p.Ala21Val	missense_variant	1/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.62C>T	p.Ala21Val	missense_variant	1/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.62C>T	p.Ala21Val	missense_variant	1/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.62C>T	p.Ala21Val	missense_variant	1/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.62C>T	p.Ala21Val	missense_variant	1/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.62C>T	p.Ala21Val	missense_variant	1/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.62C>T	p.Ala21Val	missense_variant	1/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.62C>T	p.Ala21Val	missense_variant	1/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.62C>T	p.Ala21Val	missense_variant	1/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.62C>T	p.Ala21Val	missense_variant	1/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152120 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0105

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000892 AC: 134 AN: 150184 Hom.: 1 AF XY: 0.000880 AC XY: 71 AN XY: 80650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000421

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000242

GnomAD4 exome AF: 0.000152 AC: 212 AN: 1394688 Hom.: 1 Cov.: 33 AF XY: 0.000157 AC XY: 108 AN XY: 688050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000571

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00495

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000215

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.000415

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152228 Hom.: 1 Cov.: 30 AF XY: 0.000376 AC XY: 28 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0105

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000344

ExAC AF: 0.000599 AC: 50

Asia WGS AF: 0.00145 AC: 5 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2016

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
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
MetaRNN	Benign	0.0070	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.9	.;M;.;.;M;.;.;M;.;.;.;.;M;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.050	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.35	T;T;.;.;.;.;.;.;.;.;.;T;.;.;.
Polyphen		0.60	.;P;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.16
MutPred		0.46		Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);Gain of MoRF binding (P = 0.084);
MVP		0.91
MPC		1.1
ClinPred		0.028	T
GERP RS		2.7
Varity_R		0.083
gMVP		0.33

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

Other links and lift over

dbSNP: rs15999; hg19: chr19-13616977;