2-166280374-G-A

Variant names:

• chr2-166280374-G-A
• rs771120873
• NM_001365536.1:c.2326C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001365536.1(SCN9A):​c.2326C>T​(p.Leu776Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,418,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2326C>T	p.Leu776Phe	missense_variant	Exon 14 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2326C>T	p.Leu776Phe	missense_variant	Exon 14 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2326C>T	p.Leu776Phe	missense_variant	Exon 14 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2293C>T	p.Leu765Phe	missense_variant	Exon 14 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2293C>T	p.Leu765Phe	missense_variant	Exon 14 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2293C>T	p.Leu765Phe	missense_variant	Exon 14 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 197776 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1418790 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 702498

African (AFR) AF: 0.00 AC: 0 AN: 32792

American (AMR) AF: 0.00 AC: 0 AN: 39524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.00 AC: 0 AN: 38560

South Asian (SAS) AF: 0.00 AC: 0 AN: 81252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1085542

Other (OTH) AF: 0.00 AC: 0 AN: 58786

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000834 AC: 1

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

Jun 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This sequence change replaces leucine with phenylalanine at codon 765 of the SCN9A protein (p.Leu765Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with SCN9A-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.;.;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;H;.;.;H;H;.
PhyloP100		7.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D;.;.;.;.;D;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Uncertain	0.016	D;D;.;.;.;D;.
Vest4		0.90
MutPred		0.38		Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);
MVP		0.89
MPC		0.58
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.55
gMVP		0.32
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771120873; hg19: chr2-167136884;