chr19-13299242-C-T

Position:

• chr19-13299242-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_001127222.2(CACNA1A):​c.2391G>A​(p.Met797Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,609,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.810

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 -2 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=0.14686096).
• BP6: Variant 19-13299242-C-T is Benign according to our data. Variant chr19-13299242-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2391G>A	p.Met797Ile	missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2391G>A	p.Met797Ile	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2403G>A	p.Met801Ile	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2397G>A	p.Met799Ile	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2394G>A	p.Met798Ile	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2394G>A	p.Met798Ile	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2394G>A	p.Met798Ile	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2253G>A	p.Met751Ile	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2394G>A	p.Met798Ile	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2403G>A	p.Met801Ile	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2394G>A	p.Met798Ile	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2397G>A	p.Met799Ile	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2394G>A	p.Met798Ile	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2394G>A	p.Met798Ile	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2394G>A	p.Met798Ile	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000814 AC: 2 AN: 245768 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133652

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1457006 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000243 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 09, 2020

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.024	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.0	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.13	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.35	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.17
MutPred		0.21		.;.;Loss of disorder (P = 0.0472);Loss of disorder (P = 0.0472);Loss of disorder (P = 0.0472);.;Loss of disorder (P = 0.0472);.;.;Loss of disorder (P = 0.0472);Loss of disorder (P = 0.0472);.;Loss of disorder (P = 0.0472);.;Loss of disorder (P = 0.0472);
MVP		0.79
MPC		1.2
ClinPred		0.095	T
GERP RS		2.9
Varity_R		0.32
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: rs370746809; hg19: chr19-13410056;