rs121908914

Variant names:

• chr2-166204448-A-G
• rs121908914
• NM_001365536.1:c.4415T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-166204448-A-G
• chr2-166204448-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001365536.1(SCN9A):​c.4415T>C​(p.Ile1472Thr) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1472N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.19
• Publications: 20 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 10 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, 5 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 chr2-166204448-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 446178.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 2-166204448-A-G is Pathogenic according to our data. Variant chr2-166204448-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6360.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4415T>C	p.Ile1472Thr	missense_variant	Exon 25 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4415T>C	p.Ile1472Thr	missense_variant	Exon 25 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.4415T>C	p.Ile1472Thr	missense_variant	Exon 25 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.4382T>C	p.Ile1461Thr	missense_variant	Exon 25 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.4382T>C	p.Ile1461Thr	missense_variant	Exon 25 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.000548 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN9A protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN9A function (PMID: 17145499, 18599537, 20038812, 21115638). ClinVar contains an entry for this variant (Variation ID: 6360). This missense change has been observed in individual(s) with autosomal dominant paroxysmal extreme pain disorder (PMID: 17145499). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1461 of the SCN9A protein (p.Ile1461Thr). -

Paroxysmal extreme pain disorder Pathogenic:1

Dec 07, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;D;.;.;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	4.0	.;H;.;.;H;H
PhyloP100		9.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.6	D;.;.;.;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D
Vest4		0.94
MutPred		0.58		Gain of disorder (P = 0.0205);.;Gain of disorder (P = 0.0205);.;.;.;
MVP		0.94
MPC		0.28
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.74
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908914; hg19: chr2-167060958;