2-166280565-G-T

Position:

• chr2-166280565-G-T

Variant summary

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

The NM_001365536.1(SCN9A):​c.2135C>A​(p.Pro712His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.04

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:):

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, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2135C>A	p.Pro712His	missense_variant	14/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2135C>A	p.Pro712His	missense_variant	14/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2135C>A	p.Pro712His	missense_variant	14/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2102C>A	p.Pro701His	missense_variant	14/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2102C>A	p.Pro701His	missense_variant	14/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2102C>A	p.Pro701His	missense_variant	14/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710392

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: 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	Benign	0.24
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;D;.;.;D;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H;.;.;H;H;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.3	D;D;.;.;.;D;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;T;.;.;.;D;.
Sift4G	Uncertain	0.044	D;D;.;.;.;D;.
Vest4		0.63
MutPred		0.42		Loss of glycosylation at P701 (P = 0.0215);.;Loss of glycosylation at P701 (P = 0.0215);Loss of glycosylation at P701 (P = 0.0215);.;.;Loss of glycosylation at P701 (P = 0.0215);
MVP		0.95
MPC		0.56
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.30

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: rs867106113; hg19: chr2-167137075;