2-166288543-A-T

Variant names:

• chr2-166288543-A-T
• rs199986805
• NM_001365536.1:c.1208T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001365536.1(SCN9A):​c.1208T>A​(p.Met403Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,910 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.24

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1208T>A	p.Met403Lys	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.1208T>A	p.Met403Lys	missense_variant	Exon 10 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1208T>A	p.Met403Lys	missense_variant	Exon 10 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1208T>A	p.Met403Lys	missense_variant	Exon 10 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1208T>A	p.Met403Lys	missense_variant	Exon 10 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1208T>A	p.Met403Lys	missense_variant	Exon 10 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.*72T>A		downstream_gene_variant		1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248696 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134914

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460910 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726758

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;D;.;.;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D;.;.;.;.;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Uncertain	0.0070	D;D;.;.;.;D;.
Polyphen		1.0	.;D;.;.;D;.;.
Vest4		0.59
MVP		0.93
MPC		0.70
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.85

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: rs199986805; hg19: chr2-167145053;