2-166294631-A-T

Variant names:

• chr2-166294631-A-T
• rs1553492770
• NM_001365536.1:c.933T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001365536.1(SCN9A):​c.933T>A​(p.Asp311Glu) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D311D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.933T>A	p.Asp311Glu	missense_variant	Exon 8 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.933T>A	p.Asp311Glu	missense_variant	Exon 8 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.933T>A	p.Asp311Glu	missense_variant	Exon 8 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.933T>A	p.Asp311Glu	missense_variant	Exon 8 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.933T>A	p.Asp311Glu	missense_variant	Exon 8 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.933T>A	p.Asp311Glu	missense_variant	Exon 8 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.933T>A	p.Asp311Glu	missense_variant	Exon 9 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 311 of the SCN9A protein (p.Asp311Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. 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 not expected to disrupt SCN9A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D;.;.;D;.;.;.
Eigen	Benign	0.011
Eigen_PC	Benign	0.024
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.8	L;L;L;.;L;L;.;.
PhyloP100		1.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D;.;.;.;.;D;.;.
REVEL	Pathogenic	0.74
Sift	Benign	0.097	T;.;.;.;.;T;.;.
Sift4G	Benign	0.38	T;T;.;.;.;T;.;.
Polyphen		0.75	.;P;.;.;P;.;.;.
Vest4		0.57
MVP		0.66
MPC		0.28
ClinPred		0.96	D
GERP RS		2.3
Varity_R		0.26
gMVP		0.80
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1553492770; hg19: chr2-167151141;