rs188814235

Variant names:

• chr2-166304229-A-G
• rs188814235
• NM_001365536.1:c.688+9T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001365536.1(SCN9A):​c.688+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,612,418 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.57
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 2-166304229-A-G is Benign according to our data. Variant chr2-166304229-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198152.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.688+9T>C		intron_variant	Intron 6 of 26	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.688+9T>C		intron_variant	Intron 6 of 26		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.688+9T>C		intron_variant	Intron 6 of 26	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.688+9T>C		intron_variant	Intron 6 of 26	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.597-107T>C		intron_variant	Intron 5 of 26			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.688+9T>C		intron_variant	Intron 6 of 14	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.688+9T>C		intron_variant	Intron 7 of 10	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000188 AC: 47 AN: 249596 AF XY: 0.000155

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000801 AC: 117 AN: 1460196 Hom.: 0 Cov.: 31 AF XY: 0.0000647 AC XY: 47 AN XY: 726466

African (AFR) AF: 0.00287 AC: 96 AN: 33446

American (AMR) AF: 0.0000896 AC: 4 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110648

Other (OTH) AF: 0.000249 AC: 15 AN: 60332

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152222 Hom.: 1 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74436

African (AFR) AF: 0.00236 AC: 98 AN: 41554

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000362 Hom.: 1

Bravo AF: 0.000729

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Apr 17, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN9A c.688+9T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00019 in 249596 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. To our knowledge, no occurrence of c.688+9T>C in individuals affected with Primary Erythromelalgia and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

SCN9A-related disorder Benign:1

Jun 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.76
PhyloP100		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs188814235; hg19: chr2-167160739;