NM_001365536.1:c.3121C>G

Variant names:

• chr2-166272629-G-C
• rs200163274
• NM_001365536.1:c.3121C>G

Variant summary

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

The NM_001365536.1(SCN9A):​c.3121C>G​(p.His1041Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.54

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=0.25399905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3121C>G	p.His1041Asp	missense_variant	Exon 17 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3121C>G	p.His1041Asp	missense_variant	Exon 17 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3121C>G	p.His1041Asp	missense_variant	Exon 17 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3088C>G	p.His1030Asp	missense_variant	Exon 17 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3088C>G	p.His1030Asp	missense_variant	Exon 17 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461186 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726874

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: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H1030D variant (also known as c.3088C>G), located in coding exon 16 of the SCN9A gene, results from a C to G substitution at nucleotide position 3088. The histidine at codon 1030 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Sep 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 1030 of the SCN9A protein (p.His1030Asp). This variant is present in population databases (rs200163274, gnomAD 0.007%). 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: 1472379). 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. 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	0.14
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Uncertain	0.59	.;D;.;.;D;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.35	T;.;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	.;M;.;.;M;M
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.8	D;.;.;.;.;D
REVEL	Benign	0.26
Sift	Uncertain	0.0040	D;.;.;.;.;D
Sift4G	Benign	0.12	T;T;.;.;.;T
Vest4		0.28
MutPred		0.51		Gain of phosphorylation at Y1026 (P = 0.1128);.;Gain of phosphorylation at Y1026 (P = 0.1128);Gain of phosphorylation at Y1026 (P = 0.1128);.;.;
MVP		0.41
MPC		0.29
ClinPred		0.96	D
GERP RS		3.6
Varity_R		0.62
gMVP		0.25

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: rs200163274; hg19: chr2-167129139;