rs188336294

Variant names:

• chr2-166226651-G-A
• rs188336294
• NM_001365536.1:c.4314C>T
• SCN9A p.Val1438Val

Your query was ambiguous. Multiple possible variants found:

• chr2-166226651-G-A
• chr2-166226651-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001365536.1(SCN9A):​c.4314C>T​(p.Val1438Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,589,516 control chromosomes in the GnomAD database, including 5 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 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 1.81
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 2-166226651-G-A is Benign according to our data. Variant chr2-166226651-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195816.
• BP7: Synonymous conserved (PhyloP=1.82 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.4314C>T	p.Val1438Val	synonymous	Exon 24 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.4281C>T	p.Val1427Val	synonymous	Exon 24 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.612-21544G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4314C>T	p.Val1438Val	synonymous	Exon 24 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.4314C>T	p.Val1438Val	synonymous	Exon 24 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.4281C>T	p.Val1427Val	synonymous	Exon 24 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 247 AN: 151964 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00122 AC: 278 AN: 228342 AF XY: 0.00121

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00238

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00146 AC: 2096 AN: 1437434 Hom.: 4 Cov.: 28 AF XY: 0.00146 AC XY: 1038 AN XY: 713016

African (AFR) AF: 0.00106 AC: 35 AN: 32906

American (AMR) AF: 0.00130 AC: 55 AN: 42340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 39044

South Asian (SAS) AF: 0.000113 AC: 9 AN: 79650

European-Finnish (FIN) AF: 0.00237 AC: 125 AN: 52664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00162 AC: 1782 AN: 1099862

Other (OTH) AF: 0.00151 AC: 90 AN: 59580

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152082 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74360

African (AFR) AF: 0.00161 AC: 67 AN: 41532

American (AMR) AF: 0.00353 AC: 54 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10574

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

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 67922

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

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00143

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	2	not specified (2)
-	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	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		1.8
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs188336294;

hg19: chr2-167083161;

COSMIC: COSV57611648;