NM_001365536.1:c.1549G>C

Variant names:

• chr2-166286389-C-G
• NM_001365536.1:c.1549G>C

Variant summary

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

The NM_001365536.1(SCN9A):​c.1549G>C​(p.Gly517Arg) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.680

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=0.2648198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1549G>C	p.Gly517Arg	missense_variant	Exon 11 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1549G>C	p.Gly517Arg	missense_variant	Exon 11 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1549G>C	p.Gly517Arg	missense_variant	Exon 11 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1549G>C	p.Gly517Arg	missense_variant	Exon 11 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1549G>C	p.Gly517Arg	missense_variant	Exon 11 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1549G>C	p.Gly517Arg	missense_variant	Exon 11 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 517 of the SCN9A protein (p.Gly517Arg). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	.;T;.;.;T;.;.
Eigen	Benign	-0.019
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T;.;T;T;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.1	L;L;L;.;L;L;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.86	N;.;.;.;.;N;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.017	D;.;.;.;.;D;.
Sift4G	Benign	0.19	T;T;.;.;.;T;.
Polyphen		0.024	.;B;.;.;B;.;.
Vest4		0.42
MVP		0.85
MPC		0.14
ClinPred		0.59	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-167142899;