rs200123848

Variant names:

• chr2-166238173-A-G
• rs200123848
• NM_001365536.1:c.3722T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The ENST00000642356.2(SCN9A):​c.3722T>C​(p.Met1241Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,457,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: SCN9A ENST00000642356.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000642356.2. 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.3722T>C	p.Met1241Thr	missense	Exon 20 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.3689T>C	p.Met1230Thr	missense	Exon 20 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.612-10022A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3722T>C	p.Met1241Thr	missense	Exon 20 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.3722T>C	p.Met1241Thr	missense	Exon 20 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.3689T>C	p.Met1230Thr	missense	Exon 20 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457014 Hom.: 0 Cov.: 28 AF XY: 0.00000828 AC XY: 6 AN XY: 724664

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 85526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1108870

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

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	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.80
MutPred		0.72		Loss of stability (P = 0.051)
MVP		0.82
MPC		0.32
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.73
Mutation Taster		=2/98	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: rs200123848; hg19: chr2-167094683;