rs200785571

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001365536.1(SCN9A):c.5956A>G(p.Ser1986Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,592,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1986N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.815

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.054234058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.5956A>G	p.Ser1986Gly	missense_variant	Exon 27 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.5956A>G	p.Ser1986Gly	missense_variant	Exon 27 of 27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.5956A>G	p.Ser1986Gly	missense_variant	Exon 27 of 27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.5923A>G	p.Ser1975Gly	missense_variant	Exon 27 of 27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.5923A>G	p.Ser1975Gly	missense_variant	Exon 27 of 27			ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000394

AC:

AN:

228244

AF XY:

0.0000243

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000655

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000669

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000500

AC:

AN:

1439926

Hom.:

Cov.:

AF XY:

0.0000392

AC XY:

AN XY:

714390

show subpopulations

African (AFR)

AF:

0.0000309

AC:

AN:

32318

American (AMR)

AF:

0.0000248

AC:

AN:

40296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25382

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.00

AC:

AN:

81474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

1102934

Other (OTH)

AF:

0.0000839

AC:

AN:

59566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000661

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SCN9A c.5923A>G; p.Ser1975Gly variant (rs200785571), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 471159). This variant is found in the non-Finnish European population with an allele frequency of 0.007% (8/120,012 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.279). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Apr 30, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5923A>G (p.S1975G) alteration is located in exon 27 (coding exon 26) of the SCN9A gene. This alteration results from a A to G substitution at nucleotide position 5923, causing the serine (S) at amino acid position 1975 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, 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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1975 of the SCN9A protein (p.Ser1975Gly). This variant is present in population databases (rs200785571, gnomAD 0.008%). 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: 471159). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.058

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.29

.;T;.;.;T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.53

T;.;T;T;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.054

T;T;T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.34

.;N;.;.;N;N

PhyloP100

0.81

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.7

N;.;.;.;.;N

REVEL

Benign

0.28

Sift

Benign

0.041

D;.;.;.;.;D

Sift4G

Benign

0.41

T;T;.;.;.;T

Vest4

0.036

MVP

0.30

MPC

0.11

ClinPred

0.030

GERP RS

3.4

Varity_R

0.11

gMVP

0.15

Mutation Taster

=35/65

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over