rs80356476

Positions:

• chr2-166277252-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. 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

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

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• 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 Lovd as [Pathogenic].
• 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 id is 6364.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-166277252-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2605C>T	p.Leu869Phe	missense_variant	16/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.1029+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2605C>T	p.Leu869Phe	missense_variant	16/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1707+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary erythromelalgia Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -

Computational scores

Source: dbNSFP v4.3

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;.;.;D;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;.;.;M;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.9	D;.;.;.;.;D;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.
Vest4		0.92
MutPred		0.93		Gain of catalytic residue at L858 (P = 0.0618);.;Gain of catalytic residue at L858 (P = 0.0618);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356476; hg19: chr2-167133762;