rs190664764

chr2-166251876-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001365536.1(SCN9A):c.3361C>T(p.Arg1121Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,612,016 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1121Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (28 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.427

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 2-166251876-G-A is Benign according to our data. Variant chr2-166251876-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194839.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=2}. Variant chr2-166251876-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.3361C>T	p.Arg1121Trp	missense_variant	18/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.833G>A		non_coding_transcript_exon_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.3361C>T	p.Arg1121Trp	missense_variant	18/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1511G>A		non_coding_transcript_exon_variant	14/19

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 151836 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000484

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: 0.0342

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00350 AC: 868 AN: 247866 Hom.: 11 AF XY: 0.00349 AC XY: 469 AN XY: 134450

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00351

GnomAD4 exome AF: 0.00185 AC: 2707 AN: 1460062 Hom.: 28 Cov.: 31 AF XY: 0.00181 AC XY: 1315 AN XY: 726276

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0315

Gnomad4 NFE exome AF: 0.000841

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00281 AC: 427 AN: 151954 Hom.: 5 Cov.: 32 AF XY: 0.00440 AC XY: 327 AN XY: 74272

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0342

Gnomad4 NFE AF: 0.000913

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000765 Hom.: 1

Bravo AF: 0.000378

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.000854 AC: 7

ExAC AF: 0.00318 AC: 384

EpiCase AF: 0.000712

EpiControl AF: 0.000773

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2017	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 07, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2016	- -

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
MetaRNN	Benign	0.0049	T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N;.;.;.;.;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.016	D;.;.;.;.;D
Sift4G	Uncertain	0.015	D;D;.;.;.;D
Vest4		0.29
MVP		0.71
MPC		0.42
ClinPred		0.037	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 9

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

Publications

LitVar

Other links and lift over

dbSNP: rs190664764; hg19: chr2-167108386; COSMIC: COSV57601840;