rs200682458

Variant names:

• chr2-166286474-G-A
• rs200682458
• NM_001365536.1:c.1464C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001365536.1(SCN9A):​c.1464C>T​(p.Leu488Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,682 control chromosomes in the GnomAD database, including 3 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 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11
• Conservation: PhyloP100: -3.28
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-166286474-G-A is Benign according to our data. Variant chr2-166286474-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 291185.
• BP7: Synonymous conserved (PhyloP=-3.28 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,SD 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.1464C>T	p.Leu488Leu	synonymous	Exon 11 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.1464C>T	p.Leu488Leu	synonymous	Exon 11 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1030-8091G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1464C>T	p.Leu488Leu	synonymous	Exon 11 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.1464C>T	p.Leu488Leu	synonymous	Exon 11 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.1464C>T	p.Leu488Leu	synonymous	Exon 11 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

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: 0.00110

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000446 AC: 111 AN: 249022 AF XY: 0.000481

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000922

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00111 AC: 1623 AN: 1461594 Hom.: 3 Cov.: 31 AF XY: 0.00107 AC XY: 778 AN XY: 727068

African (AFR) AF: 0.000149 AC: 5 AN: 33466

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00138 AC: 1535 AN: 1111816

Other (OTH) AF: 0.00133 AC: 80 AN: 60372

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.000485 AC XY: 36 AN XY: 74290

African (AFR) AF: 0.000266 AC: 11 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000756 Hom.: 0

Bravo AF: 0.000574

EpiCase AF: 0.000764

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	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	not specified (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)
-	-	1	SCN9A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.7
DANN	Benign	0.74
PhyloP100		-3.3
Mutation Taster		=100/0	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: rs200682458; hg19: chr2-167142984;