rs772492538

Positions:

chr2-166280534-C-G

Variant summary

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

The NM_001365536.1(SCN9A):c.2166G>C(p.Leu722Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,592,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.301

Variant links:

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]

SCN9A links:

SCN1A-AS1 (HGNC:):

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.2166G>C	p.Leu722Phe	missense_variant	14/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.2166G>C	p.Leu722Phe	missense_variant	14/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 linkuse as main transcript	c.2166G>C	p.Leu722Phe	missense_variant	14/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 linkuse as main transcript	c.2133G>C	p.Leu711Phe	missense_variant	14/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 linkuse as main transcript	c.2133G>C	p.Leu711Phe	missense_variant	14/27			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 linkuse as main transcript	c.2133G>C	p.Leu711Phe	missense_variant	14/15	1		ENSP00000413212.2	A0A0C4DG82

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000184

AC:

AN:

217000

Hom.:

AF XY:

0.0000343

AC XY:

AN XY:

116464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000216

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.0000312

AC:

AN:

1440142

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

713994

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000196

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000191

Gnomad4 OTH exome

AF:

0.0000840

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000901

Hom.:

ExAC

AF:

0.0000333

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2023	Observed in patients with epilepsy; however, further clinical information was not provided (Hussein et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Hussein2023[medRxiv]) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The p.L711F variant (also known as c.2133G>C), located in coding exon 13 of the SCN9A gene, results from a G to C substitution at nucleotide position 2133. The leucine at codon 711 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, 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

Jan 19, 2024

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 711 of the SCN9A protein (p.Leu711Phe). This variant is present in population databases (rs772492538, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 575125). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SCN9A protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;D;.;.;D;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

D;.;D;D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Uncertain

0.72

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.6

.;H;.;.;H;H;.

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

D;.;.;.;.;D;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;.;.;.;D;.

Sift4G

Benign

0.078

T;T;.;.;.;T;.

Vest4

0.67

MutPred

0.44

Loss of catalytic residue at L711 (P = 0.0053);.;Loss of catalytic residue at L711 (P = 0.0053);Loss of catalytic residue at L711 (P = 0.0053);.;.;Loss of catalytic residue at L711 (P = 0.0053);

MVP

0.83

MPC

0.58

ClinPred

0.99

GERP RS

3.0

Varity_R

0.65

gMVP

0.21

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over