2-165090847-A-G

Position:

• chr2-165090847-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Moderate PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006922.4(SCN3A):​c.5306T>C​(p.Val1769Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.32

Genes affected

SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript NM_006922.4 (SCN3A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN3A. . Gene score misZ 4.618 (greater than the threshold 3.09). Trascript score misZ 6.3553 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, epilepsy, familial focal, with variable foci 4, developmental and epileptic encephalopathy, 62.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 2-165090847-A-G is Pathogenic according to our data. Variant chr2-165090847-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN3A	NM_006922.4	c.5306T>C	p.Val1769Ala	missense_variant	28/28	ENST00000283254.12	NP_008853.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12	c.5306T>C	p.Val1769Ala	missense_variant	28/28	1	NM_006922.4	ENSP00000283254	P1
	ENST00000638199.1	n.1144-273A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 62 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Dec 21, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 17, 2020	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2016

- -

Early infantile epileptic encephalopathy with suppression bursts Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D;D;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0080	D;D;.;D
Polyphen		1.0, 0.83	.;D;.;P
Vest4		0.56
MutPred		0.68		Loss of stability (P = 0.0344);Loss of stability (P = 0.0344);.;.;
MVP		0.90
MPC		1.9
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.71
gMVP		0.96

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: rs1553517274; hg19: chr2-165947357;