chr19-13286722-T-C

Position:

• chr19-13286722-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001127222.2(CACNA1A):​c.3334A>G​(p.Met1112Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,597,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.11

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.08642647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3334A>G	p.Met1112Val	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.3334A>G	p.Met1112Val	missense_variant	20/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3346A>G	p.Met1116Val	missense_variant	20/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3340A>G	p.Met1114Val	missense_variant	20/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3337A>G	p.Met1113Val	missense_variant	20/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3337A>G	p.Met1113Val	missense_variant	20/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3337A>G	p.Met1113Val	missense_variant	20/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3196A>G	p.Met1066Val	missense_variant	19/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3337A>G	p.Met1113Val	missense_variant	20/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3346A>G	p.Met1116Val	missense_variant	20/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3337A>G	p.Met1113Val	missense_variant	20/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3340A>G	p.Met1114Val	missense_variant	20/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3337A>G	p.Met1113Val	missense_variant	20/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3337A>G	p.Met1113Val	missense_variant	20/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3337A>G	p.Met1113Val	missense_variant	20/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151692 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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445342 Hom.: 0 Cov.: 35 AF XY: 0.00000279 AC XY: 2 AN XY: 716898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151692 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74046

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: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Dec 11, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1113 of the CACNA1A protein (p.Met1113Val). This variant is not present in population databases (gnomAD no frequency). 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: 1941026). 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

The c.3337A>G (p.M1113V) alteration is located in exon 20 (coding exon 20) of the CACNA1A gene. This alteration results from a A to G substitution at nucleotide position 3337, causing the methionine (M) at amino acid position 1113 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.026
DANN	Benign	0.46
DEOGEN2	Benign	0.0028	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.61	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.086	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.0	.;.;.;.;N;.;.;.;.;.;.;.;N;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.11	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.98	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.65	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.070
MutPred		0.29		.;.;Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;Gain of sheet (P = 0.0266);.;.;Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;Gain of sheet (P = 0.0266);.;Gain of sheet (P = 0.0266);
MVP		0.51
MPC		0.013
ClinPred		0.033	T
GERP RS		-0.58
Varity_R		0.017
gMVP		0.44

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: rs755317765; hg19: chr19-13397536;