rs111558968

chr2-166198860-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365536.1(SCN9A):c.5779C>T(p.Leu1927Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000659 in 1,613,748 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 6 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.43

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004175842).

BP6

Variant 2-166198860-G-A is Benign according to our data. Variant chr2-166198860-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166198860-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0029 (442/152222) while in subpopulation AFR AF= 0.00963 (400/41526). AF 95% confidence interval is 0.00885. There are 4 homozygotes in gnomad4. There are 190 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.5779C>T	p.Leu1927Phe	missense_variant	27/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1 linkuse as main transcript	n.432-779G>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.5779C>T	p.Leu1927Phe	missense_variant	27/27		NM_001365536.1	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1110-779G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00289

AC:

439

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00959

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.000279

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000766

AC:

191

AN:

249406

Hom.:

AF XY:

0.000547

AC XY:

AN XY:

135282

show subpopulations

Gnomad AFR exome

AF:

0.00962

Gnomad AMR exome

AF:

0.000667

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:

0.000124

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.000426

AC:

622

AN:

1461526

Hom.:

Cov.:

AF XY:

0.000385

AC XY:

280

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.0115

Gnomad4 AMR exome

AF:

0.000761

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000881

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.00290

AC:

442

AN:

152222

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00963

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000775

Hom.:

Bravo

AF:

0.00332

ESP6500AA

AF:

0.00802

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000984

AC:

119

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	SCN9A: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 12, 2015

- -

Primary erythromelalgia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 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. -

Inherited Erythromelalgia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Paroxysmal extreme pain disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

Cadd

Benign

Dann

Benign

0.95

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.24

T;.;T;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T;T;T

MetaSVM

Benign

-0.39

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

N;N;.;.;.;N

REVEL

Benign

0.27

Sift

Benign

0.59

T;T;.;.;.;T

Sift4G

Benign

0.71

T;T;.;.;.;T

Vest4

0.054

MVP

0.54

MPC

0.13

ClinPred

0.013

GERP RS

4.2

Varity_R

0.074

gMVP

0.21

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

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