2-165090170-C-T

Position:

• chr2-165090170-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006922.4(SCN3A):​c.5983G>A​(p.Val1995Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,658 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.104

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 Likely_benign. 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), 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.055143386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN3A	NM_006922.4	c.5983G>A	p.Val1995Ile	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.5983G>A	p.Val1995Ile	missense_variant	28/28	1	NM_006922.4	ENSP00000283254	P1
	ENST00000638199.1	n.1144-950C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435658 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 712116

Gnomad4 AFR exome AF: 0.0000300

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: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2021

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.79
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.47	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	-0.20	N;N;.;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.37	N;N;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.37	T;T;.;T
Sift4G	Benign	0.42	T;T;.;T
Polyphen		0.0020, 0.0	.;B;.;B
Vest4		0.0090
MutPred		0.19		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);.;.;
MVP		0.15
MPC		0.55
ClinPred		0.15	T
GERP RS		6.0
Varity_R		0.040
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-165946680;