2-165090206-T-G

Position:

• chr2-165090206-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_006922.4(SCN3A):​c.5947A>C​(p.Lys1983Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,453,296 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 0.000014 (1 hom.)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.36

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]

ENSG00000236283 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• 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=0.11830023).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000144 (21/1453296) while in subpopulation SAS AF= 0.000246 (21/85468). AF 95% confidence interval is 0.000164. There are 1 homozygotes in gnomad4_exome. There are 15 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN3A	NM_006922.4	c.5947A>C	p.Lys1983Gln	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.5947A>C	p.Lys1983Gln	missense_variant	28/28	1	NM_006922.4	ENSP00000283254.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000167 AC: 4 AN: 239438 Hom.: 0 AF XY: 0.0000232 AC XY: 3 AN XY: 129084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1453296 Hom.: 1 Cov.: 31 AF XY: 0.0000208 AC XY: 15 AN XY: 722248

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: 0.000246

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, familial focal, with variable foci 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The c.5947A>C (p.Lys1983Gln) missense variant in SCN3A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.001%) in the gnomAD and novel in 1000 genome database. The amino acid Lys at position 1983 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Lys1983Gln in SCN3A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 22, 2022

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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SCN3A-related conditions. This variant is present in population databases (rs774354894, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1983 of the SCN3A protein (p.Lys1983Gln). -

Developmental and epileptic encephalopathy, 62 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.K1983Q in SCN3A (NM_006922.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is observed in 4/29,646 (0.0135%) alleles from individuals of South Asian background in gnomAD Exomes. There is a small physicochemical difference between lysine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. Insilico tools predict a damaging effect (SIFT). For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.26	T;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.0	N;N;.;.
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.24	N;N;.;N
REVEL	Benign	0.29
Sift	Benign	0.35	T;T;.;T
Sift4G	Benign	0.38	T;T;.;T
Polyphen		0.041, 0.023	.;B;.;B
Vest4		0.29
MutPred		0.23		Loss of methylation at K1983 (P = 0.0025);Loss of methylation at K1983 (P = 0.0025);.;.;
MVP		0.77
MPC		1.6
ClinPred		0.084	T
GERP RS		6.0
Varity_R		0.10
gMVP		0.32

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: rs774354894; hg19: chr2-165946716;