rs121908912

chr2-166228972-C-Achr2-166228972-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001365536.1(SCN9A):c.3925G>T(p.Val1309Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1309D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166228971-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 6357.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-166228972-C-A is Pathogenic according to our data. Variant chr2-166228972-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6358.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-166228972-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.3925G>T	p.Val1309Phe	missense_variant, splice_region_variant	22/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.612-19223C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.3925G>T	p.Val1309Phe	missense_variant, splice_region_variant	22/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1290-19223C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453624 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000385

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Paroxysmal extreme pain disorder Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 07, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;.;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D
Vest4		0.85
MutPred		0.79		Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);.;.;.;
MVP		0.94
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.020		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: rs121908912; hg19: chr2-167085482;