chr2-166198800-C-G

Position:

• chr2-166198800-C-G

Variant summary

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

The NM_001365536.1(SCN9A):​c.5839G>C​(p.Asp1947His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D1947D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.514

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.5839G>C	p.Asp1947His	missense_variant	27/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.432-839C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.5839G>C	p.Asp1947His	missense_variant	27/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1110-839C>G		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

Dec 13, 2017

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SCN9A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 1936 of the SCN9A protein (p.Asp1936His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;D;.;.;D;.
Eigen	Benign	-0.028
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.7	.;M;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.8	D;.;.;.;.;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;.;.;.;D
Sift4G	Uncertain	0.0090	D;D;.;.;.;D
Vest4		0.17
MutPred		0.28		Loss of loop (P = 0.0288);.;Loss of loop (P = 0.0288);.;.;.;
MVP		0.82
MPC		0.55
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.28
gMVP		0.30

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: rs1553472744; hg19: chr2-167055310;