rs201666606

chr19-13299132-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001127222.2(CACNA1A):c.2501A>C(p.Asn834Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000645 in 1,612,944 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 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 3.93

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.22211501).
• BP6: Variant 19-13299132-T-G is Benign according to our data. Variant chr19-13299132-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 582956.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.2501A>C	p.Asn834Thr	missense_variant	19/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2501A>C	p.Asn834Thr	missense_variant	19/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000767 AC: 19 AN: 247840 Hom.: 0 AF XY: 0.0000520 AC XY: 7 AN XY: 134698

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.0000980

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000637 AC: 93 AN: 1460734 Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 726734

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74428

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000977 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2022	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2016

The p.N835T variant (also known as c.2504A>C), located in coding exon 19 of the CACNA1A gene, results from an A to C substitution at nucleotide position 2504. The asparagine at codon 835 is replaced by threonine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs201666606. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.01% (1/12234) total alleles studied and 0.01% (1/8256) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 08, 2024

Variant summary: CACNA1A c.2504A>C (p.Asn835Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 1612944 control chromosomes (ie. 104 individuals) in the gnomAD database (v4). This frequency suggests this variant is not likely to be associated with a highly penetrant autosomal dominant disorder. To our knowledge, no occurrence of c.2504A>C in individuals affected with Early Infantile Epileptic Encephalopathy or Episodic Ataxia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 582956). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
Sift4G	Benign	0.37	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.45
MVP		0.90
MPC		2.1
ClinPred		0.22	T
GERP RS		3.8
Varity_R		0.27
gMVP		0.84

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: rs201666606; hg19: chr19-13409946;