2-166281810-TAA-TA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.1975-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,374,896 control chromosomes in the GnomAD database, including 24 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00080 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (21 hom.)
• Consequence: SCN9A NM_001365536.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• 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-TA-T is Benign according to our data. Variant chr2-166281810-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000797 (119/149306) while in subpopulation SAS AF = 0.0204 (96/4700). AF 95% confidence interval is 0.0171. There are 3 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,SD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.1975-3delT		splice_region intron	N/A	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.1942-3delT		splice_region intron	N/A	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1029+4573delA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1975-3delT		splice_region intron	N/A	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.1975-3delT		splice_region intron	N/A	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.1942-3delT		splice_region intron	N/A	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.000771 AC: 115 AN: 149216 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.000201

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0131 AC: 1958 AN: 148910 AF XY: 0.0138

Gnomad AFR exome AF: 0.00649

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.0132

Gnomad FIN exome AF: 0.00929

Gnomad NFE exome AF: 0.00738

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.00547 AC: 6702 AN: 1225590 Hom.: 21 Cov.: 29 AF XY: 0.00607 AC XY: 3689 AN XY: 607628

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

African (AFR) AF: 0.00527 AC: 142 AN: 26964

American (AMR) AF: 0.0112 AC: 366 AN: 32598

Ashkenazi Jewish (ASJ) AF: 0.00689 AC: 143 AN: 20740

East Asian (EAS) AF: 0.00490 AC: 154 AN: 31424

South Asian (SAS) AF: 0.0287 AC: 1936 AN: 67456

European-Finnish (FIN) AF: 0.00582 AC: 255 AN: 43836

Middle Eastern (MID) AF: 0.00282 AC: 14 AN: 4972

European-Non Finnish (NFE) AF: 0.00358 AC: 3392 AN: 947966

Other (OTH) AF: 0.00604 AC: 300 AN: 49634

⚠️ 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: 0.000797 AC: 119 AN: 149306 Hom.: 3 Cov.: 31 AF XY: 0.00104 AC XY: 76 AN XY: 72850

African (AFR) AF: 0.000294 AC: 12 AN: 40834

American (AMR) AF: 0.00 AC: 0 AN: 14926

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

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5128

South Asian (SAS) AF: 0.0204 AC: 96 AN: 4700

European-Finnish (FIN) AF: 0.000201 AC: 2 AN: 9926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67074

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0208 Hom.: 30

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Congenital Indifference to Pain (1)
-	-	1	Febrile seizures, familial (1)
-	-	1	Generalized epilepsy with febrile seizures plus (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Inherited Erythromelalgia (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Severe myoclonic epilepsy in infancy (1)
-	-	1	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26
Mutation Taster		=99/1	polymorphism

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; COSMIC: COSV57603390; COSMIC: COSV57603390;