NM_001365536.1:c.2190G>C

Variant names:

• chr2-166280510-C-G
• rs202055175
• NM_001365536.1:c.2190G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.2190G>C​(p.Trp730Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,589,184 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W730L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.91
• Publications: 3 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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.03022027).
• BP6: Variant 2-166280510-C-G is Benign according to our data. Variant chr2-166280510-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00316 (480/152112) while in subpopulation AFR AF = 0.0108 (448/41484). AF 95% confidence interval is 0.00997. There are 3 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.2190G>C	p.Trp730Cys	missense	Exon 14 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.2157G>C	p.Trp719Cys	missense	Exon 14 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1029+3263C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.2190G>C	p.Trp730Cys	missense	Exon 14 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.2190G>C	p.Trp730Cys	missense	Exon 14 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.2157G>C	p.Trp719Cys	missense	Exon 14 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 478 AN: 151994 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000721 AC: 153 AN: 212310 AF XY: 0.000492

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000454

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000327

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000264 AC: 379 AN: 1437072 Hom.: 2 Cov.: 31 AF XY: 0.000213 AC XY: 152 AN XY: 712274

African (AFR) AF: 0.00902 AC: 299 AN: 33156

American (AMR) AF: 0.000552 AC: 23 AN: 41682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25534

East Asian (EAS) AF: 0.00 AC: 0 AN: 39092

South Asian (SAS) AF: 0.00 AC: 0 AN: 82798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51932

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5730

European-Non Finnish (NFE) AF: 0.0000264 AC: 29 AN: 1097710

Other (OTH) AF: 0.000437 AC: 26 AN: 59438

GnomAD4 genome AF: 0.00316 AC: 480 AN: 152112 Hom.: 3 Cov.: 33 AF XY: 0.00309 AC XY: 230 AN XY: 74376

African (AFR) AF: 0.0108 AC: 448 AN: 41484

American (AMR) AF: 0.00151 AC: 23 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67986

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000579 Hom.: 0

Bravo AF: 0.00359

ESP6500AA AF: 0.0119 AC: 43

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000873 AC: 105

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	Inherited Erythromelalgia (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.030	T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.94
MutPred		0.61		Loss of MoRF binding (P = 0.018)
MVP		0.84
MPC		0.70
ClinPred		0.19	T
GERP RS		5.9
Varity_R		0.60
gMVP		0.66
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202055175; hg19: chr2-167137020; COSMIC: COSV57617846; COSMIC: COSV57617846;