2-166281810-T-TAA

Variant names:

• chr2-166281810-T-TAA
• rs35888674
• NM_001365536.1:c.1975-4_1975-3dupTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001365536.1(SCN9A):​c.1975-4_1975-3dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,426,264 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: SCN9A NM_001365536.1 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 2-166281810-T-TAA is Benign according to our data. Variant chr2-166281810-T-TAA is described in ClinVar as Likely_benign. ClinVar VariationId is 696802.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1975-4_1975-3dupTT		splice_region intron	N/A	NP_001352465.1
	SCN9A	NM_002977.4		c.1942-4_1942-3dupTT		splice_region intron	N/A	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1029+4572_1029+4573dupAA		intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.0000402 AC: 6 AN: 149284 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000246

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000745

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000181 AC: 27 AN: 148910 AF XY: 0.000136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000125

Gnomad ASJ exome AF: 0.000585

Gnomad EAS exome AF: 0.000101

Gnomad FIN exome AF: 0.0000720

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.000311

GnomAD4 exome AF: 0.000254 AC: 324 AN: 1276980 Hom.: 1 Cov.: 29 AF XY: 0.000232 AC XY: 147 AN XY: 633768

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000107 AC: 3 AN: 28156

American (AMR) AF: 0.000175 AC: 6 AN: 34340

Ashkenazi Jewish (ASJ) AF: 0.000413 AC: 9 AN: 21772

East Asian (EAS) AF: 0.0000599 AC: 2 AN: 33372

South Asian (SAS) AF: 0.000323 AC: 23 AN: 71144

European-Finnish (FIN) AF: 0.000131 AC: 6 AN: 45900

Middle Eastern (MID) AF: 0.00117 AC: 6 AN: 5136

European-Non Finnish (NFE) AF: 0.000262 AC: 258 AN: 985236

Other (OTH) AF: 0.000212 AC: 11 AN: 51924

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000402 AC: 6 AN: 149284 Hom.: 0 Cov.: 31 AF XY: 0.0000412 AC XY: 3 AN XY: 72792

African (AFR) AF: 0.0000246 AC: 1 AN: 40722

American (AMR) AF: 0.00 AC: 0 AN: 14918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000745 AC: 5 AN: 67122

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.000625 Hom.: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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

Splicing

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

Other links and lift over

dbSNP: rs35888674; hg19: chr2-167138320;