19-13209374-C-T

Position:

• chr19-13209374-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001127222.2(CACNA1A):​c.6464G>A​(p.Arg2155His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000324 in 1,389,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2155L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.90

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 Likely_benign. Variant got -4 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=0.29916927).
• BS2: High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6464G>A	p.Arg2155His	missense_variant	45/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6464G>A	p.Arg2155His	missense_variant	45/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6482G>A	p.Arg2161His	missense_variant	46/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6470G>A	p.Arg2157His	missense_variant	45/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6467G>A	p.Arg2156His	missense_variant	45/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6467G>A	p.Arg2156His	missense_variant	45/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6431G>A	p.Arg2144His	missense_variant	44/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6326G>A	p.Arg2109His	missense_variant	44/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6467G>A	p.Arg2156His	missense_variant	45/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6482G>A	p.Arg2161His	missense_variant	46/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6473G>A	p.Arg2158His	missense_variant	46/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6470G>A	p.Arg2157His	missense_variant	45/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6467G>A	p.Arg2156His	missense_variant	45/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6467G>A	p.Arg2156His	missense_variant	45/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6431G>A	p.Arg2144His	missense_variant	44/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*730G>A		non_coding_transcript_exon_variant	9/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*730G>A		3_prime_UTR_variant	9/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000348 AC: 43 AN: 1236970 Hom.: 0 Cov.: 32 AF XY: 0.0000335 AC XY: 20 AN XY: 597166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000328

Gnomad4 SAS exome AF: 0.0000191

Gnomad4 FIN exome AF: 0.0000234

Gnomad4 NFE exome AF: 0.0000400

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32038460) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2156 of the CACNA1A protein (p.Arg2156His). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 422167). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2017

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	0.15
BayesDel_addAF	Benign	0.0028	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.17	.;T;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.3	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.11	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.16	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.24
MutPred		0.18		.;.;Loss of MoRF binding (P = 0.0638);Loss of MoRF binding (P = 0.0638);Loss of MoRF binding (P = 0.0638);.;.;Loss of MoRF binding (P = 0.0638);.;.;.;.;Loss of MoRF binding (P = 0.0638);.;.;.;.;.;
MVP		0.84
MPC		0.35
ClinPred		0.70	D
GERP RS		3.1
Varity_R		0.088
gMVP		0.32

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: rs572722130; hg19: chr19-13320188;