2-166198929-G-T

Variant names:

• chr2-166198929-G-T
• rs372083483
• NM_001365536.1:c.5710C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001365536.1(SCN9A):​c.5710C>A​(p.Arg1904Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1904H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.5710C>A	p.Arg1904Ser	missense	Exon 27 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.5677C>A	p.Arg1893Ser	missense	Exon 27 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.432-710G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.5710C>A	p.Arg1904Ser	missense	Exon 27 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.5710C>A	p.Arg1904Ser	missense	Exon 27 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.5677C>A	p.Arg1893Ser	missense	Exon 27 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.7	L
PhyloP100		3.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Vest4		0.26
MutPred		0.51		Gain of phosphorylation at R1893 (P = 0.012)
MVP		0.66
MPC		0.15
ClinPred		0.87	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.69
Mutation Taster		=48/52	disease causing

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: rs372083483; hg19: chr2-167055439; COSMIC: COSV57629012;