rs182650126

chr2-166280452-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001365536.1(SCN9A):c.2248A>G(p.Ile750Val) variant causes a missense change. The variant allele was found at a frequency of 0.00346 in 1,589,074 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (10 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:14
• Conservation: PhyloP100: 4.15

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012462795).
• BP6: Variant 2-166280452-T-C is Benign according to our data. Variant chr2-166280452-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157597.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=12, Uncertain_significance=1}. Variant chr2-166280452-T-C is described in Lovd as [Likely_benign]. Variant chr2-166280452-T-C is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAdExome at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.2248A>G	p.Ile750Val	missense_variant	14/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.1029+3205T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.2248A>G	p.Ile750Val	missense_variant	14/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1707+3205T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152086 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00245 AC: 515 AN: 210268 Hom.: 2 AF XY: 0.00234 AC XY: 264 AN XY: 112770

Gnomad AFR exome AF: 0.000696

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.000323

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000683

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00354 AC: 5089 AN: 1436870 Hom.: 10 Cov.: 30 AF XY: 0.00346 AC XY: 2463 AN XY: 712154

Gnomad4 AFR exome AF: 0.000331

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000847

Gnomad4 FIN exome AF: 0.00400

Gnomad4 NFE exome AF: 0.00413

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152204 Hom.: 1 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74408

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00311 Hom.: 2

Bravo AF: 0.00237

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000820 AC: 3

ESP6500EA AF: 0.00404 AC: 33

ExAC AF: 0.00199 AC: 240

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SCN9A: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	This variant is associated with the following publications: (PMID: 19763161, 24820863, 24737233, 32707200, 22539570, 27301361, 28073787, 28235406, 23891399, 29176367, 27608006, 27916648, 28488083, 30478917, 31664448, 22826602, 21698661) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 28, 2017	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 19, 2015	- -

Small fiber neuropathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2014

- -

Primary erythromelalgia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inherited Erythromelalgia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

SCN9A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Paroxysmal extreme pain disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.89	N;.;.;.;.;N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.022	D;.;.;.;.;D;.
Sift4G	Uncertain	0.039	D;D;.;.;.;D;.
Vest4		0.49
MVP		0.71
MPC		0.11
ClinPred		0.032	T
GERP RS		5.9
Varity_R		0.27
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs182650126; hg19: chr2-167136962; COSMIC: COSV105146574; COSMIC: COSV105146574;