rs182650126

Variant names:

• chr2-166280452-T-C
• rs182650126
• NM_001365536.1:c.2248A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001365536.1(SCN9A):​c.2248A>G​(p.Ile750Val) variant causes a missense change. The variant allele was found at a frequency of 0.00346 in 1,589,074 control chromosomes in the GnomAD database, including 11 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 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (10 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:15
• Conservation: PhyloP100: 4.15
• Publications: 37 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012462795).
• BP6: Variant 2-166280452-T-C is Benign according to our data. Variant chr2-166280452-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157597.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.2248A>G	p.Ile750Val	missense	Exon 14 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.2215A>G	p.Ile739Val	missense	Exon 14 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1029+3205T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.2248A>G	p.Ile750Val	missense	Exon 14 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.2248A>G	p.Ile750Val	missense	Exon 14 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.2215A>G	p.Ile739Val	missense	Exon 14 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152086 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00245 AC: 515 AN: 210268 AF XY: 0.00234

Gnomad AFR exome AF: 0.000696

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.000323

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00354 AC: 5089 AN: 1436870 Hom.: 10 Cov.: 30 AF XY: 0.00346 AC XY: 2463 AN XY: 712154

African (AFR) AF: 0.000331 AC: 11 AN: 33186

American (AMR) AF: 0.00262 AC: 108 AN: 41218

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 4 AN: 25628

East Asian (EAS) AF: 0.00 AC: 0 AN: 39086

South Asian (SAS) AF: 0.000847 AC: 70 AN: 82682

European-Finnish (FIN) AF: 0.00400 AC: 208 AN: 52058

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5726

European-Non Finnish (NFE) AF: 0.00413 AC: 4529 AN: 1097798

Other (OTH) AF: 0.00259 AC: 154 AN: 59488

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152204 Hom.: 1 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74408

African (AFR) AF: 0.000650 AC: 27 AN: 41508

American (AMR) AF: 0.00458 AC: 70 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00378 AC: 257 AN: 68010

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00262 Hom.: 6

Bravo AF: 0.00237

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000820 AC: 3

ESP6500EA AF: 0.00404 AC: 33

ExAC AF: 0.00199 AC: 240

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	4	not specified (4)
-	-	1	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Inherited Erythromelalgia (1)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)
-	-	1	SCN9A-related disorder (1)
1	-	-	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.012	T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.039	D
Vest4		0.49
MVP		0.71
MPC		0.11
ClinPred		0.032	T
GERP RS		5.9
Varity_R		0.27
gMVP		0.29
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs182650126; hg19: chr2-167136962; COSMIC: COSV105146574; COSMIC: COSV105146574;