2-166304325-A-T

Variant names:

• chr2-166304325-A-T
• rs80356465
• NM_001365536.1:c.601T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.601T>A​(p.Leu201Ile) 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 benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L201V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0200
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22379518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.601T>A	p.Leu201Ile	missense_variant	Exon 6 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.601T>A	p.Leu201Ile	missense_variant	Exon 6 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.601T>A	p.Leu201Ile	missense_variant	Exon 6 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.601T>A	p.Leu201Ile	missense_variant	Exon 6 of 27	5		ENSP00000386306.1
SCN9A	ENST00000454569.6	c.601T>A	p.Leu201Ile	missense_variant	Exon 6 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.601T>A	p.Leu201Ile	missense_variant	Exon 7 of 11	1		ENSP00000393141.2
SCN9A	ENST00000645907.1	c.597-203T>A		intron_variant	Intron 5 of 26			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.601T>A (p.L201I) alteration is located in exon 6 (coding exon 5) of the SCN9A gene. This alteration results from a T to A substitution at nucleotide position 601, causing the leucine (L) at amino acid position 201 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.42	.;T;T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.81	T;.;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	-0.025	N;N;N;.;.
PhyloP100		0.020
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.7	N;.;.;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.17	T;.;.;.;.
Sift4G	Benign	0.56	T;T;.;.;.
Vest4		0.35
MutPred		0.62		Gain of catalytic residue at L201 (P = 0.3556);Gain of catalytic residue at L201 (P = 0.3556);Gain of catalytic residue at L201 (P = 0.3556);Gain of catalytic residue at L201 (P = 0.3556);Gain of catalytic residue at L201 (P = 0.3556);
MVP		0.67
MPC		0.13
ClinPred		0.076	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.37
Mutation Taster		=50/50

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: rs80356465; hg19: chr2-167160835;