rs1060502051

chr2-166198822-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):c.5817G>T(p.Glu1939Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1939K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.431

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13279036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.5817G>T	p.Glu1939Asp	missense_variant	27/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.432-817C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.5817G>T	p.Glu1939Asp	missense_variant	27/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1110-817C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 18, 2016

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN9A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This sequence change replaces glutamic acid with aspartic acid at codon 1928 of the SCN9A protein (p.Glu1928Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	17
Dann	Benign	0.93
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;.;T;T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;.;.;.;.;N
REVEL	Benign	0.24
Sift	Benign	0.19	T;.;.;.;.;T
Sift4G	Benign	0.23	T;T;.;.;.;T
Vest4		0.051
MutPred		0.18		Gain of helix (P = 0.0117);.;Gain of helix (P = 0.0117);.;.;.;
MVP		0.54
MPC		0.10
ClinPred		0.071	T
GERP RS		2.4
Varity_R		0.078
gMVP		0.24

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: rs1060502051; hg19: chr2-167055332; COSMIC: COSV57605677;