19-13286646-G-T

Position:

• chr19-13286646-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001127222.2(CACNA1A):​c.3410C>A​(p.Pro1137His) variant causes a missense change. The variant allele was found at a frequency of 0.0000162 in 1,544,566 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1137A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.35

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 -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=0.19751742).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3410C>A	p.Pro1137His	missense_variant	20/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3410C>A	p.Pro1137His	missense_variant	20/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3422C>A	p.Pro1141His	missense_variant	20/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3416C>A	p.Pro1139His	missense_variant	20/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3413C>A	p.Pro1138His	missense_variant	20/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3413C>A	p.Pro1138His	missense_variant	20/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3413C>A	p.Pro1138His	missense_variant	20/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3272C>A	p.Pro1091His	missense_variant	19/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3413C>A	p.Pro1138His	missense_variant	20/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3422C>A	p.Pro1141His	missense_variant	20/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3413C>A	p.Pro1138His	missense_variant	20/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3416C>A	p.Pro1139His	missense_variant	20/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3413C>A	p.Pro1138His	missense_variant	20/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3413C>A	p.Pro1138His	missense_variant	20/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3413C>A	p.Pro1138His	missense_variant	20/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151924 Hom.: 0 Cov.: 30

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000261 AC: 5 AN: 191438 Hom.: 0 AF XY: 0.0000392 AC XY: 4 AN XY: 101924

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000247

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 24 AN: 1392642 Hom.: 0 Cov.: 35 AF XY: 0.0000219 AC XY: 15 AN XY: 685316

Gnomad4 AFR exome AF: 0.0000320

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000201

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.0000349

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151924 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74208

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 25, 2020

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. 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. This variant has not been reported in the literature in individuals with CACNA1A-related conditions. This variant is present in population databases (rs200333359, ExAC 0.02%). This sequence change replaces proline with histidine at codon 1138 of the CACNA1A protein (p.Pro1138His). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.4	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.8	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.073	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.48
MutPred		0.21		.;.;Loss of glycosylation at P1138 (P = 0.0032);Loss of glycosylation at P1138 (P = 0.0032);Loss of glycosylation at P1138 (P = 0.0032);.;Loss of glycosylation at P1138 (P = 0.0032);.;.;Loss of glycosylation at P1138 (P = 0.0032);Loss of glycosylation at P1138 (P = 0.0032);.;Loss of glycosylation at P1138 (P = 0.0032);.;Loss of glycosylation at P1138 (P = 0.0032);
MVP		0.75
MPC		0.095
ClinPred		0.70	D
GERP RS		5.1
Varity_R		0.29
gMVP		0.47

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: rs200333359; hg19: chr19-13397460; COSMIC: COSV100803137; COSMIC: COSV100803137;