2-166272625-G-C

Variant names:

• chr2-166272625-G-C
• rs757989638
• NM_001365536.1:c.3125C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001365536.1(SCN9A):​c.3125C>G​(p.Thr1042Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1042I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.20
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.3125C>G	p.Thr1042Arg	missense	Exon 17 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.3092C>G	p.Thr1031Arg	missense	Exon 17 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.870-4463G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3125C>G	p.Thr1042Arg	missense	Exon 17 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.3125C>G	p.Thr1042Arg	missense	Exon 17 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.3092C>G	p.Thr1031Arg	missense	Exon 17 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.23	T
Vest4		0.67
MutPred		0.45		Gain of MoRF binding (P = 0.0668)
MVP		0.75
MPC		0.58
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.50
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs757989638; hg19: chr2-167129135;