2-166306531-G-T

Position:

• chr2-166306531-G-T

Variant summary

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

The NM_001365536.1(SCN9A):​c.446C>A​(p.Pro149Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.76

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]

SCN9A (HGNC:):

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, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.446C>A	p.Pro149Gln	missense_variant	4/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.446C>A	p.Pro149Gln	missense_variant	4/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.446C>A	p.Pro149Gln	missense_variant	4/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.446C>A	p.Pro149Gln	missense_variant	4/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.446C>A	p.Pro149Gln	missense_variant	4/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.446C>A	p.Pro149Gln	missense_variant	4/15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.446C>A	p.Pro149Gln	missense_variant	5/11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419530 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 703196

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: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Febrile seizures, familial, 3b Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Sep 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.82	.;D;.;.;D;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M;M;.;M;M;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.0	D;D;.;.;.;D;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;.;.;.;D;.;.
Sift4G	Uncertain	0.0040	D;D;.;.;.;D;.;.
Polyphen		0.83	.;P;.;.;P;.;.;.
Vest4		0.81
MVP		0.92
MPC		0.43
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs121908921; hg19: chr2-167163041;