dbSNP rs80356470: SCN9A:p.Ser241Thr (chr2-166303270-A-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001365536.1(SCN9A):c.721T>A(p.Ser241Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S241S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1U:1O:1

Conservation

PhyloP100: 9.32

Publications

41 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001365536.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

PP5

Variant 2-166303270-A-T is Pathogenic according to our data. Variant chr2-166303270-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6351.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.721T>A	p.Ser241Thr	missense_variant	Exon 7 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SCN9A	ENST00000642356.2 link	c.721T>A	p.Ser241Thr	missense_variant	Exon 7 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11 link	c.721T>A	p.Ser241Thr	missense_variant	Exon 7 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5 link	c.721T>A	p.Ser241Thr	missense_variant	Exon 7 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1 link	c.721T>A	p.Ser241Thr	missense_variant	Exon 7 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6 link	c.721T>A	p.Ser241Thr	missense_variant	Exon 7 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2 link	c.721T>A	p.Ser241Thr	missense_variant	Exon 8 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Primary erythromelalgia

Pathogenic:1Uncertain:1Other:1

Oct 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Reutter Lab, Institute of Human Genetics, University Hospital Bonn

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

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

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

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

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;M;M;.;M;M;.;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.9

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

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.95

MVP

0.91

MPC

0.54

ClinPred

0.99

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.83

Mutation Taster

=1/99

disease causing (ClinVar)

(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

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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