rs3750904

chr2-166198883-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):c.5756A>G(p.Asp1919Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,720 control chromosomes in the GnomAD database, including 3,560 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (486 hom., cov: 32)
  • Exomes 𝑓: 0.017 (3074 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.40

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]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015889108).
• BP6: Variant 2-166198883-T-C is Benign according to our data. Variant chr2-166198883-T-C is described in ClinVar as [Benign]. Clinvar id is 94092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166198883-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.5756A>G	p.Asp1919Gly	missense_variant	27/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.432-756T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.5756A>G	p.Asp1919Gly	missense_variant	27/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1110-756T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4504 AN: 152186 Hom.: 482 Cov.: 32

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0624 AC: 15587 AN: 249890 Hom.: 2400 AF XY: 0.0497 AC XY: 6732 AN XY: 135538

Gnomad AFR exome AF: 0.00600

Gnomad AMR exome AF: 0.340

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.00993

Gnomad FIN exome AF: 0.000925

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0175 AC: 25546 AN: 1461416 Hom.: 3074 Cov.: 32 AF XY: 0.0159 AC XY: 11530 AN XY: 727030

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.00984

Gnomad4 FIN exome AF: 0.000974

Gnomad4 NFE exome AF: 0.00317

Gnomad4 OTH exome AF: 0.0221

GnomAD4 genome AF: 0.0296 AC: 4515 AN: 152304 Hom.: 486 Cov.: 32 AF XY: 0.0330 AC XY: 2455 AN XY: 74474

Gnomad4 AFR AF: 0.00618

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.0147

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00416

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0173 Hom.: 369

Bravo AF: 0.0460

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00459 AC: 18

ESP6500EA AF: 0.00529 AC: 44

ExAC AF: 0.0489 AC: 5914

Asia WGS AF: 0.0740 AC: 255 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00279

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Primary erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

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

Feb 01, 2024

- -

Small fiber neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Paroxysmal extreme pain disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	23
Dann	Benign	0.97
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.69	T;.;T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.54	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;.;.;.;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.031	D;.;.;.;.;D
Sift4G	Benign	0.097	T;T;.;.;.;T
Vest4		0.10
MPC		0.15
ClinPred		0.0092	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.49

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

Other links and lift over

dbSNP: rs3750904; hg19: chr2-167055393; COSMIC: COSV57602689;