chr2-166228713-C-G

Variant names:

• chr2-166228713-C-G
• rs764682998
• NM_001365536.1:c.4184G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001365536.1(SCN9A):​c.4184G>C​(p.Gly1395Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1395D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.4184G>C	p.Gly1395Ala	missense	Exon 22 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.4151G>C	p.Gly1384Ala	missense	Exon 22 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.612-19482C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4184G>C	p.Gly1395Ala	missense	Exon 22 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.4184G>C	p.Gly1395Ala	missense	Exon 22 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.4151G>C	p.Gly1384Ala	missense	Exon 22 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460224 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726194

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110816

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.5	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.36	T
Vest4		0.83
MutPred		0.85		Loss of helix (P = 0.1299)
MVP		0.85
MPC		0.47
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.91
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs764682998; hg19: chr2-167085223; COSMIC: COSV100313471;