rs759003928

Positions:

chr2-166242647-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PM2BP6

The NM_001365536.1(SCN9A):c.3482G>A(p.Trp1161Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,548,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: -0.516

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_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 2-166242647-C-T is Benign according to our data. Variant chr2-166242647-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471114.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.3482G>A	p.Trp1161Ter	stop_gained	19/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1 linkuse as main transcript	n.612-5548C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.3482G>A	p.Trp1161Ter	stop_gained	19/27		NM_001365536.1	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1290-5548C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000146

AC:

AN:

157238

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

82688

show subpopulations

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 SAS exome

AF:

0.000488

Gnomad FIN exome

AF:

0.000119

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

234

AN:

1396888

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

120

AN XY:

688952

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.0000282

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000369

Gnomad4 FIN exome

AF:

0.0000609

Gnomad4 NFE exome

AF:

0.000172

Gnomad4 OTH exome

AF:

0.000259

GnomAD4 genome

AF:

0.000118

AC:

AN:

151978

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000133

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2020	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2023

Unlikely to be causative of SCN9A-related neuropathic pain syndromes (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 05, 2020

ACMG classification criteria: PVS1 -

Generalized epilepsy with febrile seizures plus, type 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 01, 2018

The SCN9A c.3449G>A (p.Trp1150Ter) variant is a stop-gained variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for SCN9A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Primary erythromelalgia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Paroxysmal extreme pain disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.049

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.85

GERP RS

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: 9

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