chr2-166280572-A-G

Position:

• chr2-166280572-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001365536.1(SCN9A):​c.2128T>C​(p.Cys710Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000629 in 1,430,260 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C710Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166280571-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2128T>C	p.Cys710Arg	missense_variant	14/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.1029+3325A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2128T>C	p.Cys710Arg	missense_variant	14/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1707+3325A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000498 AC: 1 AN: 200830 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 107432

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000629 AC: 9 AN: 1430260 Hom.: 0 Cov.: 31 AF XY: 0.00000424 AC XY: 3 AN XY: 708298

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: 0.00000731

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000837 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 20, 2017

This sequence change replaces cysteine with arginine at codon 699 of the SCN9A protein (p.Cys699Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs766287092, ExAC 0.005%). This variant has not been reported in the literature in individuals with SCN9A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	.;D;.;.;D;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H;.;.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-12	D;.;.;.;.;D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Uncertain	0.0020	D;D;.;.;.;D;.
Vest4		0.93
MutPred		0.59		Gain of disorder (P = 0.0038);.;Gain of disorder (P = 0.0038);Gain of disorder (P = 0.0038);.;.;Gain of disorder (P = 0.0038);
MVP		0.96
MPC		0.75
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766287092; hg19: chr2-167137082;