2-166288474-A-G

Variant names:

• chr2-166288474-A-G
• rs200415928
• NM_001365536.1:c.1277T>C

Variant summary

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

The NM_001365536.1(SCN9A):​c.1277T>C​(p.Met426Thr) 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. 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. M426K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.17
• 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: MetaRNN computational evidence supports a deleterious effect, 0.789

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.1277T>C	p.Met426Thr	missense	Exon 10 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.1277T>C	p.Met426Thr	missense	Exon 10 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1030-6091A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1277T>C	p.Met426Thr	missense	Exon 10 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.1277T>C	p.Met426Thr	missense	Exon 10 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.1277T>C	p.Met426Thr	missense	Exon 10 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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	0.66
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.0	L
PhyloP100		5.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.45	T
Polyphen		0.96	D
Vest4		0.34
MVP		0.76
MPC		0.50
ClinPred		0.92	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.41
Mutation Taster		=17/83	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: rs200415928; hg19: chr2-167144984;