rs3750904

Variant names:

• chr2-166198883-T-C
• rs3750904
• NM_001365536.1:c.5756A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.5756A>G​(p.Asp1919Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,720 control chromosomes in the GnomAD database, including 3,560 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (486 hom., cov: 32)
  • Exomes 𝑓: 0.017 (3074 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.40
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015889108).
• BP6: Variant 2-166198883-T-C is Benign according to our data. Variant chr2-166198883-T-C is described in ClinVar as Benign. ClinVar VariationId is 94092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

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.5756A>G	p.Asp1919Gly	missense	Exon 27 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.5723A>G	p.Asp1908Gly	missense	Exon 27 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.432-756T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.5756A>G	p.Asp1919Gly	missense	Exon 27 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.5756A>G	p.Asp1919Gly	missense	Exon 27 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.5723A>G	p.Asp1908Gly	missense	Exon 27 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4504 AN: 152186 Hom.: 482 Cov.: 32

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0624 AC: 15587 AN: 249890 AF XY: 0.0497

Gnomad AFR exome AF: 0.00600

Gnomad AMR exome AF: 0.340

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.000925

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0175 AC: 25546 AN: 1461416 Hom.: 3074 Cov.: 32 AF XY: 0.0159 AC XY: 11530 AN XY: 727030

African (AFR) AF: 0.00379 AC: 127 AN: 33476

American (AMR) AF: 0.324 AC: 14493 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26136

East Asian (EAS) AF: 0.127 AC: 5057 AN: 39692

South Asian (SAS) AF: 0.00984 AC: 849 AN: 86252

European-Finnish (FIN) AF: 0.000974 AC: 52 AN: 53396

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5764

European-Non Finnish (NFE) AF: 0.00317 AC: 3528 AN: 1111632

Other (OTH) AF: 0.0221 AC: 1333 AN: 60360

GnomAD4 genome AF: 0.0296 AC: 4515 AN: 152304 Hom.: 486 Cov.: 32 AF XY: 0.0330 AC XY: 2455 AN XY: 74474

African (AFR) AF: 0.00618 AC: 257 AN: 41576

American (AMR) AF: 0.204 AC: 3114 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.137 AC: 710 AN: 5174

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4832

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00416 AC: 283 AN: 68016

Other (OTH) AF: 0.0284 AC: 60 AN: 2116

Alfa AF: 0.0191 Hom.: 595

Bravo AF: 0.0460

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00459 AC: 18

ESP6500EA AF: 0.00529 AC: 44

ExAC AF: 0.0489 AC: 5914

Asia WGS AF: 0.0740 AC: 255 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	not provided (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)
-	-	1	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Benign	0.031	D
Sift4G	Benign	0.097	T
Vest4		0.10
MPC		0.15
ClinPred		0.0092	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.49
Mutation Taster		=86/14	polymorphism (auto)

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: rs3750904; hg19: chr2-167055393; COSMIC: COSV57602689;