rs201354321

Positions:

chr2-166284823-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001365536.1(SCN9A):c.1604C>T(p.Ser535Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000344 in 1,600,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. S535A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense, splice_region

Scores

Splicing: ADA: 0.9769

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 9.52

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.1604C>T	p.Ser535Leu	missense_variant, splice_region_variant	12/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1 linkuse as main transcript	n.1029+7576G>A		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.1604C>T	p.Ser535Leu	missense_variant, splice_region_variant	12/27		NM_001365536.1	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1707+7576G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000129

AC:

AN:

232786

Hom.:

AF XY:

0.00

AC XY:

AN XY:

126788

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000284

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000345

AC:

AN:

1448406

Hom.:

Cov.:

AF XY:

0.0000347

AC XY:

AN XY:

720096

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000406

Gnomad4 OTH exome

AF:

0.0000835

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000555

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 26, 2017	The p.Ser535Leu variant (rs201354321) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.002 percent (identified on 4 out of 260,912 chromosomes). The serine at position 535 is highly conserved considering 12 species (Alamut v2.9.0) and computational analyses of the effects of the p.Ser535Leu variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Ser535Leu variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Primary erythromelalgia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Aug 18, 2018

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.1604C>T (p.S535L) alteration is located in exon 12 (coding exon 11) of the SCN9A gene. This alteration results from a C to T substitution at nucleotide position 1604, causing the serine (S) at amino acid position 535 to be replaced by a leucine (L). The alteration is ultra rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the SCN9A c.1604C>T alteration was observed in 0.002% (4/264,180) of total alleles studied. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.S535 amino acid is conserved in available vertebrate species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.S535L alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 535 of the SCN9A protein (p.Ser535Leu). This variant is present in population databases (rs201354321, gnomAD 0.003%). 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: 538480). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

0.26

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.85

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

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.2

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

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

Sift4G

Benign

0.10

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

Polyphen

1.0

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

Vest4

0.84

MVP

0.83

MPC

0.38

ClinPred

0.86

GERP RS

5.5

Varity_R

0.51

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.81

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