rs1467872202

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001365536.1(SCN9A):c.3502G>T(p.Val1168Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65

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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.3502G>T	p.Val1168Phe	missense_variant	Exon 19 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.3502G>T	p.Val1168Phe	missense_variant	Exon 19 of 27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.3502G>T	p.Val1168Phe	missense_variant	Exon 19 of 27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.3469G>T	p.Val1157Phe	missense_variant	Exon 19 of 27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.3469G>T	p.Val1157Phe	missense_variant	Exon 19 of 27			ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000624

AC:

AN:

160274

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000403

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

7.14e-7

AC:

AN:

1400302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690846

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31686

American (AMR)

AF:

0.0000279

AC:

AN:

35788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25150

East Asian (EAS)

AF:

0.00

AC:

AN:

35918

South Asian (SAS)

AF:

0.00

AC:

AN:

79224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079234

Other (OTH)

AF:

0.00

AC:

AN:

58092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Jun 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 471115). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1157 of the SCN9A protein (p.Val1157Phe). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

.;D;.;.;D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

D;.;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Pathogenic

3.2

.;M;.;.;M;M

PhyloP100

1.7

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.9

D;.;.;.;.;D

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;.;.;.;.;D

Sift4G

Benign

0.35

T;T;.;.;.;T

Vest4

0.49

MutPred

0.74

Loss of catalytic residue at V1157 (P = 0.0057);.;Loss of catalytic residue at V1157 (P = 0.0057);Loss of catalytic residue at V1157 (P = 0.0057);.;.;

MVP

0.86

MPC

0.62

ClinPred

0.97

GERP RS

4.7

Varity_R

0.70

gMVP

0.45

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over