rs73019664

chr2-166242620-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001365536.1(SCN9A):c.3509T>C(p.Ile1170Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,553,390 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.682

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008853674).
• BP6: Variant 2-166242620-A-G is Benign according to our data. Variant chr2-166242620-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130263.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.3509T>C	p.Ile1170Thr	missense_variant	19/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.612-5575A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.3509T>C	p.Ile1170Thr	missense_variant	19/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1290-5575A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000397 AC: 64 AN: 161404 Hom.: 0 AF XY: 0.000283 AC XY: 24 AN XY: 84848

Gnomad AFR exome AF: 0.00386

Gnomad AMR exome AF: 0.000241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.0000314

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 212 AN: 1401224 Hom.: 0 Cov.: 30 AF XY: 0.000133 AC XY: 92 AN XY: 691394

Gnomad4 AFR exome AF: 0.00372

Gnomad4 AMR exome AF: 0.000223

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.0000378

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00000926

Gnomad4 OTH exome AF: 0.000310

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74380

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00287 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000295 AC: 32

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2018	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2023	Variant summary: SCN9A c.3476T>C (p.Ile1159Thr) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 161404 control chromosomes (gnomAD). c.3476T>C has been reported in the literature in an individual(s) affected with clinically-suspected neuropathy without strong evidence of causality (Antoniadi_2015). This report does not provide unequivocal conclusions about association of the variant with Primary Erythromelalgia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26392352). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely benign (n=3) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SCN9A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	14
Dann	Benign	0.82
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.80	T;.;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0089	T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.84	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N;.;.;.;.;N
REVEL	Benign	0.24
Sift	Benign	0.54	T;.;.;.;.;T
Sift4G	Benign	0.69	T;T;.;.;.;T
Vest4		0.081
MVP		0.33
MPC		0.15
ClinPred		0.0054	T
GERP RS		-0.48
Varity_R		0.14
gMVP		0.20

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: rs73019664; hg19: chr2-167099130;