rs80356476

Variant names:

• chr2-166277252-G-A
• rs80356476
• NM_001365536.1:c.2605C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001365536.1(SCN9A):​c.2605C>T​(p.Leu869Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L869H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.34
• Publications: 30 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001365536.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166277251-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6349.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 2-166277252-G-A is Pathogenic according to our data. Variant chr2-166277252-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6364.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2605C>T	p.Leu869Phe	missense	Exon 16 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.2572C>T	p.Leu858Phe	missense	Exon 16 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1029+5G>A		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.2605C>T	p.Leu869Phe	missense	Exon 16 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.2605C>T	p.Leu869Phe	missense	Exon 16 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.2572C>T	p.Leu858Phe	missense	Exon 16 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Primary erythromelalgia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.92
MutPred		0.93		Gain of catalytic residue at L858 (P = 0.0618)
MVP		0.86
MPC		0.58
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.63
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs80356476; hg19: chr2-167133762;