2-166293316-T-C

Position:

• chr2-166293316-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001365536.1(SCN9A):​c.1022A>G​(p.Tyr341Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.01

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1022A>G	p.Tyr341Cys	missense_variant	9/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1022A>G	p.Tyr341Cys	missense_variant	9/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1022A>G	p.Tyr341Cys	missense_variant	9/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1022A>G	p.Tyr341Cys	missense_variant	9/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1022A>G	p.Tyr341Cys	missense_variant	9/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1022A>G	p.Tyr341Cys	missense_variant	9/15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.1022A>G	p.Tyr341Cys	missense_variant	10/11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455728 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 723328

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1022A>G (p.Y341C) alteration is located in exon 9 (coding exon 8) of the SCN9A gene. This alteration results from a A to G substitution at nucleotide position 1022, causing the tyrosine (Y) at amino acid position 341 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 341 of the SCN9A protein (p.Tyr341Cys). ClinVar contains an entry for this variant (Variation ID: 245823). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN9A protein function. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2015

The Y341C variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The Y341C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position between the S5 and S6 transmembrane segments of the first homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants have not been reported in this region of the protein in association with SCN9A-related neuropathy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;H;.;H;H;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.7	D;.;.;.;.;D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;D;.;.
Polyphen		1.0	.;D;.;.;D;.;.;.
Vest4		0.93
MVP		0.97
MPC		0.63
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.91

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: rs374280444; hg19: chr2-167149826;