2-166198819-G-C

Position:

• chr2-166198819-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365536.1(SCN9A):​c.5820C>G​(p.Asn1940Lys) 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.67

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41875595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.5820C>G	p.Asn1940Lys	missense_variant	27/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.432-820G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.5820C>G	p.Asn1940Lys	missense_variant	27/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1110-820G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary erythromelalgia;C0751122:Severe myoclonic epilepsy in infancy;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive;C2751778: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

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Sep 03, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1929 of the SCN9A protein (p.Asn1929Lys). 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: 471155). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN9A protein function. 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	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.56	.;D;.;.;D;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.074
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.42	T;T;T;T;T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.8	.;L;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.2	D;.;.;.;.;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0060	D;.;.;.;.;D
Sift4G	Benign	0.33	T;T;.;.;.;T
Vest4		0.18
MutPred		0.29		Gain of ubiquitination at N1929 (P = 7e-04);.;Gain of ubiquitination at N1929 (P = 7e-04);.;.;.;
MVP		0.66
MPC		0.14
ClinPred		0.74	D
GERP RS		3.3
Varity_R		0.34
gMVP		0.34

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: rs371454107; hg19: chr2-167055329;