rs200266532

Variant names:

• chr2-166228692-A-C
• NM_001365536.1:c.4205T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-166228692-A-C
• chr2-166228692-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001365536.1(SCN9A):​c.4205T>G​(p.Val1402Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense, splice_region
• Scores: Splicing: ADA: 0.2836
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4205T>G	p.Val1402Gly	missense_variant, splice_region_variant	Exon 22 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4205T>G	p.Val1402Gly	missense_variant, splice_region_variant	Exon 22 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.4205T>G	p.Val1402Gly	missense_variant, splice_region_variant	Exon 22 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.4172T>G	p.Val1391Gly	missense_variant, splice_region_variant	Exon 22 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.4172T>G	p.Val1391Gly	missense_variant, splice_region_variant	Exon 22 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456532 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723982

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

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	0.94
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;.;T;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;H;H
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.7	D;.;.;.;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D
Vest4		0.59
MutPred		0.76		Loss of stability (P = 0.0167);.;Loss of stability (P = 0.0167);.;.;.;
MVP		0.95
MPC		0.62
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.28
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 1

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: chr2-167085202;