2-166288474-A-T

Position:

chr2-166288474-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001365536.1(SCN9A):c.1277T>A(p.Met426Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000862 in 1,612,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 5.17

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:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062217236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.1277T>A	p.Met426Lys	missense_variant	10/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.1277T>A	p.Met426Lys	missense_variant	10/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.1277T>A	p.Met426Lys	missense_variant	10/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.1277T>A	p.Met426Lys	missense_variant	10/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.1277T>A	p.Met426Lys	missense_variant	10/27			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 link	c.1277T>A	p.Met426Lys	missense_variant	10/15	1		ENSP00000413212.2	A0A0C4DG82

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000137

AC:

AN:

248746

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

134938

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000479

AC:

AN:

1460540

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.000201

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000453

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000251

Hom.:

Bravo

AF:

0.000442

ESP6500AA

AF:

0.000815

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000141

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The p.M426K variant (also known as c.1277T>A), located in coding exon 9 of the SCN9A gene, results from a T to A substitution at nucleotide position 1277. The methionine at codon 426 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of primary erythermalgia/small fiber neuropathy and paroxysmal extreme pain disorder (PEPD); however, its contribution to the development of congenital insensitivity to pain (CIP) and hereditary sensory autonomic neuropathy type II (HSAN2D) is uncertain. -

Primary erythromelalgia;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SCN9A NM_002977 exon 10 p.Met426Lys (c.1277T>A): This variant has not been reported in the literature but is present in 0.1% (46/24002) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs200415928). This variant is present in ClinVar (Variation ID:415032). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Primary erythromelalgia;C0751122:Severe myoclonic epilepsy in infancy;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive;C2751778:Generalized epilepsy with febrile seizures plus, type 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 11, 2017

SCN9A NM_002977.3 exon 10 p.Met426Lys (c.1277T>A): This variant has not been reported in the literature but is present in 0.1% (46/24002) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs200415928). This variant is present in ClinVar (Variation ID:415032). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

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

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.062

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.5

L;L;L;.;L;L;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.1

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.028

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

Sift4G

Benign

0.31

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

Polyphen

0.42

.;B;.;.;B;.;.

Vest4

0.39

MVP

0.75

MPC

0.21

ClinPred

0.052

GERP RS

5.7

Varity_R

0.68

gMVP

0.66

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

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