rs201269793

Variant names:

• chr19-13285126-C-A
• rs201269793
• NM_001127222.2:c.3634G>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.3634G>T​(p.Asp1212Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,858 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).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.24

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.19524652).
• BP6: Variant 19-13285126-C-A is Benign according to our data. Variant chr19-13285126-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432567.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000789 (12/152158) while in subpopulation AMR AF= 0.000589 (9/15274). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3634G>T	p.Asp1212Tyr	missense_variant	Exon 21 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3634G>T	p.Asp1212Tyr	missense_variant	Exon 21 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3646G>T	p.Asp1216Tyr	missense_variant	Exon 21 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3640G>T	p.Asp1214Tyr	missense_variant	Exon 21 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3637G>T	p.Asp1213Tyr	missense_variant	Exon 21 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3637G>T	p.Asp1213Tyr	missense_variant	Exon 21 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3637G>T	p.Asp1213Tyr	missense_variant	Exon 21 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3496G>T	p.Asp1166Tyr	missense_variant	Exon 20 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3637G>T	p.Asp1213Tyr	missense_variant	Exon 21 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3646G>T	p.Asp1216Tyr	missense_variant	Exon 21 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3637G>T	p.Asp1213Tyr	missense_variant	Exon 21 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3640G>T	p.Asp1214Tyr	missense_variant	Exon 21 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3637G>T	p.Asp1213Tyr	missense_variant	Exon 21 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3637G>T	p.Asp1213Tyr	missense_variant	Exon 21 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3637G>T	p.Asp1213Tyr	missense_variant	Exon 21 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000324 AC: 8 AN: 246850 Hom.: 0 AF XY: 0.0000373 AC XY: 5 AN XY: 134134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Feb 05, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Aug 28, 2023

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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.9	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.0080	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.027	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.61
MutPred		0.24		.;.;Gain of phosphorylation at D1213 (P = 0.0202);Gain of phosphorylation at D1213 (P = 0.0202);Gain of phosphorylation at D1213 (P = 0.0202);.;Gain of phosphorylation at D1213 (P = 0.0202);.;.;Gain of phosphorylation at D1213 (P = 0.0202);Gain of phosphorylation at D1213 (P = 0.0202);.;Gain of phosphorylation at D1213 (P = 0.0202);.;Gain of phosphorylation at D1213 (P = 0.0202);
MVP		0.64
MPC		0.19
ClinPred		0.48	T
GERP RS		4.9
Varity_R		0.20
gMVP		0.56

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: rs201269793; hg19: chr19-13395940;