2-166281810-T-TA

Variant names:

• chr2-166281810-T-TA
• rs35888674
• NM_001365536.1:c.1975-3dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.1975-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0796 in 1,386,398 control chromosomes in the GnomAD database, including 1,634 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (411 hom., cov: 31)
  • Exomes 𝑓: 0.081 (1223 hom.)
• Consequence: SCN9A NM_001365536.1 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.261
• Publications: 4 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-166281810-T-TA is Benign according to our data. Variant chr2-166281810-T-TA is described in ClinVar as Benign. ClinVar VariationId is 167661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0743 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.1975-3dupT		splice_region intron	N/A	NP_001352465.1
	SCN9A	NM_002977.4		c.1942-3dupT		splice_region intron	N/A	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1029+4573dupA		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1975-3_1975-2insT		splice_region intron	N/A	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.1975-3_1975-2insT		splice_region intron	N/A	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.1942-3_1942-2insT		splice_region intron	N/A	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10299 AN: 149218 Hom.: 411 Cov.: 31

Gnomad AFR AF: 0.0586

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0688

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.0458

Gnomad FIN AF: 0.0729

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.0803

GnomAD2 exomes AF: 0.0930 AC: 13856 AN: 148910 AF XY: 0.0953

Gnomad AFR exome AF: 0.0813

Gnomad AMR exome AF: 0.0736

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.0305

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0995

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.0809 AC: 100070 AN: 1237090 Hom.: 1223 Cov.: 29 AF XY: 0.0813 AC XY: 49907 AN XY: 613726

African (AFR) AF: 0.0727 AC: 1978 AN: 27218

American (AMR) AF: 0.0513 AC: 1710 AN: 33328

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 2656 AN: 21098

East Asian (EAS) AF: 0.0508 AC: 1631 AN: 32106

South Asian (SAS) AF: 0.0643 AC: 4417 AN: 68710

European-Finnish (FIN) AF: 0.0756 AC: 3364 AN: 44476

Middle Eastern (MID) AF: 0.120 AC: 602 AN: 5008

European-Non Finnish (NFE) AF: 0.0832 AC: 79476 AN: 954910

Other (OTH) AF: 0.0843 AC: 4236 AN: 50236

GnomAD4 genome AF: 0.0690 AC: 10308 AN: 149308 Hom.: 411 Cov.: 31 AF XY: 0.0681 AC XY: 4960 AN XY: 72860

African (AFR) AF: 0.0587 AC: 2397 AN: 40824

American (AMR) AF: 0.0686 AC: 1024 AN: 14934

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 396 AN: 3432

East Asian (EAS) AF: 0.0221 AC: 113 AN: 5124

South Asian (SAS) AF: 0.0462 AC: 217 AN: 4698

European-Finnish (FIN) AF: 0.0729 AC: 723 AN: 9924

Middle Eastern (MID) AF: 0.145 AC: 42 AN: 290

European-Non Finnish (NFE) AF: 0.0761 AC: 5104 AN: 67094

Other (OTH) AF: 0.0797 AC: 166 AN: 2084

Alfa AF: 0.0500 Hom.: 30

Bravo AF: 0.0667

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 12, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Inherited Erythromelalgia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary erythromelalgia;C0751122:Severe myoclonic epilepsy in infancy;C2751778:Generalized epilepsy with febrile seizures plus, type 7 Benign:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: reference population

Generalized epilepsy with febrile seizures plus Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital Indifference to Pain Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Paroxysmal extreme pain disorder Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Febrile seizures, familial Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Severe myoclonic epilepsy in infancy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35888674; hg19: chr2-167138320;