chr2-166278265-T-A

Position:

• chr2-166278265-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.2392A>T​(p.Met798Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. M798V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16703561).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2392A>T	p.Met798Leu	missense_variant	15/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.1029+1018T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2392A>T	p.Met798Leu	missense_variant	15/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1707+1018T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459534 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725988

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2023

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 787 of the SCN9A protein (p.Met787Leu). 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. ClinVar contains an entry for this variant (Variation ID: 2062983). 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	Benign	0.13
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.84
DEOGEN2	Uncertain	0.49	.;T;.;.;T;.;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;.;T;T;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.051	D
MutationAssessor	Benign	-1.7	.;N;.;.;N;N;.;.
MutationTaster	Benign	0.76	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;.;.;.;.;N;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.38	T;.;.;.;.;T;.;.
Sift4G	Benign	1.0	T;T;.;.;.;T;.;.
Vest4		0.34
MutPred		0.58		Gain of catalytic residue at M787 (P = 0.0249);.;Gain of catalytic residue at M787 (P = 0.0249);Gain of catalytic residue at M787 (P = 0.0249);.;.;.;Gain of catalytic residue at M787 (P = 0.0249);
MVP		0.60
MPC		0.11
ClinPred		0.53	D
GERP RS		4.0
Varity_R		0.28
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149707354; hg19: chr2-167134775;