2-165090166-C-G

Position:

• chr2-165090166-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. 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: 0.0000021 (0 hom.)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11

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 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), 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=0.21614543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN3A	NM_006922.4	c.5987G>C	p.Arg1996Thr	missense_variant	28/28	ENST00000283254.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN3A	ENST00000283254.12	c.5987G>C	p.Arg1996Thr	missense_variant	28/28	1	NM_006922.4	P1
	ENST00000638199.1	n.1144-954C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000468 AC: 1 AN: 213730 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 114352

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2022

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). This variant has not been reported in the literature in individuals affected with SCN3A-related conditions. 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). 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. -

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;.;.
MutationTaster	Benign	0.82	N;N;N;N
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

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: rs1283747930; hg19: chr2-165946676;