2-165090166-C-G

Variant names:

• chr2-165090166-C-G
• rs1283747930
• NM_006922.4:c.5987G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006922.4(SCN3A):​c.5987G>C​(p.Arg1996Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,433,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.0000021 (0 hom.)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11
• Publications: 0 publications found

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]

SCN3A Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• developmental and epileptic encephalopathy, 62

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy, familial focal, with variable foci 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236283 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21614543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN3A	NM_006922.4	c.5987G>C	p.Arg1996Thr	missense_variant	Exon 28 of 28	ENST00000283254.12	NP_008853.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12	c.5987G>C	p.Arg1996Thr	missense_variant	Exon 28 of 28	1	NM_006922.4	ENSP00000283254.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000468 AC: 1 AN: 213730 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000622

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1433282 Hom.: 0 Cov.: 29 AF XY: 0.00000281 AC XY: 2 AN XY: 710746

African (AFR) AF: 0.00 AC: 0 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 40598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.0000762 AC: 3 AN: 39348

South Asian (SAS) AF: 0.00 AC: 0 AN: 83814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093572

Other (OTH) AF: 0.00 AC: 0 AN: 59208

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with SCN3A-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1429785). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1996 of the SCN3A protein (p.Arg1996Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.69	N;N;.;.
PhyloP100		2.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	N;N;.;N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Benign	0.064	T;T;.;T
Polyphen		0.97, 0.0	.;D;.;B
Vest4		0.17
MutPred		0.31		Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);.;.;
MVP		0.31
MPC		1.1
ClinPred		0.19	T
GERP RS		4.2
Varity_R		0.20
gMVP		0.50
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs1283747930; hg19: chr2-165946676;