rs1553497961

Variant names:

• chr2-166311525-A-C
• rs1553497961
• NM_001365536.1:c.232T>G

Variant summary

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

The NM_001365536.1(SCN9A):​c.232T>G​(p.Leu78Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0500
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.232T>G	p.Leu78Val	missense	Exon 2 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.232T>G	p.Leu78Val	missense	Exon 2 of 27	NP_002968.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.232T>G	p.Leu78Val	missense	Exon 2 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.232T>G	p.Leu78Val	missense	Exon 2 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.232T>G	p.Leu78Val	missense	Exon 2 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458656 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725594

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110252

Other (OTH) AF: 0.00 AC: 0 AN: 60196

GnomAD4 genome Cov.: 24

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	Benign	0.16
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.0091
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.42	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-0.050
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.22	T
Vest4		0.38
MutPred		0.54		Loss of stability (P = 0.0709)
MVP		0.70
MPC		0.33
ClinPred		0.96	D
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.18
Mutation Taster		=64/36	polymorphism

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: rs1553497961; hg19: chr2-167168035;