rs73969684

Variant names:

• chr2-166305834-C-G
• rs73969684
• NM_001365536.1:c.554G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-166305834-C-G
• chr2-166305834-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001365536.1(SCN9A):​c.554G>C​(p.Arg185Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,380 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. R185C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• Publications: 28 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: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.554G>C	p.Arg185Pro	missense_variant	Exon 5 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.554G>C	p.Arg185Pro	missense_variant	Exon 5 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.554G>C	p.Arg185Pro	missense_variant	Exon 5 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.554G>C	p.Arg185Pro	missense_variant	Exon 5 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.554G>C	p.Arg185Pro	missense_variant	Exon 5 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.554G>C	p.Arg185Pro	missense_variant	Exon 5 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.554G>C	p.Arg185Pro	missense_variant	Exon 6 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249044 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461380 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111612

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H;H;H;.;H;H;.;.
PhyloP100		6.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.8	D;.;.;.;.;D;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.;.
Polyphen		1.0	.;D;.;.;D;.;.;.
Vest4		0.96
MVP		0.95
MPC		0.67
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.98
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs73969684; hg19: chr2-167162344;