2-166288566-G-C

Variant names:

• chr2-166288566-G-C
• rs80356471
• NM_001365536.1:c.1185C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001365536.1(SCN9A):​c.1185C>G​(p.Asn395Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N395I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.239
• Publications: 20 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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 2-166288566-G-C is Pathogenic according to our data. Variant chr2-166288566-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 245897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1185C>G	p.Asn395Lys	missense_variant	Exon 10 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1185C>G	p.Asn395Lys	missense_variant	Exon 10 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1185C>G	p.Asn395Lys	missense_variant	Exon 10 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1185C>G	p.Asn395Lys	missense_variant	Exon 10 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1185C>G	p.Asn395Lys	missense_variant	Exon 10 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1185C>G	p.Asn395Lys	missense_variant	Exon 10 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.*49C>G		downstream_gene_variant		1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SCN9A-related disorder Pathogenic:1

Aug 16, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1185C>G (p.Asn395Lys) variant affects a highly conserved amino acid located within the local anesthetic binding site and is predicted by multiple in silico tools to have a deleterious effect on protein function (PMID: 17430993). This variant has been previously reported as a heterozygous change in a family with erythermalgia (PMID: 17263810). A different nucleotide substitution resulting in the same amino change has also been reported as a heterozygous change in a family with erythermalgia (PMID: 15955112). Functional studies suggest that this variant leads to altered channel function and altered lidocaine binding (PMID: 17430993). The c.1185C>G (p.Asn395Lys) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Based on the available evidence, c.1185C>G (p.Asn395Lys) is classified as Likely Pathogenic. -

not provided Pathogenic:1

Aug 24, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N395K missense variant in the SCN9A gene has been reported previously in association with erythermalgia (Zhang et al., 2007). Functional studies show that the N395 residue, which is located in the local anesthetic binding site, is critical for lidocaine binding, and N395K was associated with altered channel function and altered lidocaine binding (Sheets et al., 2007). The N395K variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a semi-conservative amino acid substitution, which occurs at a position in the protein that is conserved across species. Additionally, a different nucleotide substitution (c.1185 C>A) resulting in the same amino acid substitution (N395K) has also been published in association with primary erythermalgia (Drenth et al., 2005). Therefore, the presence of the N395K variant is consistent with a diagnosis of an SCN9A-related disorder -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H;H;H;.;H;H;.
PhyloP100		0.24
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.9	D;.;.;.;.;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;D;.
Polyphen		1.0	.;D;.;.;D;.;.
Vest4		0.98
MVP		0.94
MPC		0.60
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80356471; hg19: chr2-167145076;