rs200805909

chr2-166281736-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365536.1(SCN9A):c.2047C>G(p.Pro683Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 1,461,074 control chromosomes in the GnomAD database, including 1 homozygotes. 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. P683L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (1 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.2047C>G	p.Pro683Ala	missense_variant	13/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.1029+4489G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.2047C>G	p.Pro683Ala	missense_variant	13/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1707+4489G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000482 AC: 12 AN: 248892 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135028

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: 0.0000929

Gnomad NFE exome AF: 0.0000710

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461074 Hom.: 1 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726844

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: 0.000169

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000993 AC: 12

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

Invitae

Oct 03, 2017

This sequence change replaces proline with alanine at codon 672 of the SCN9A protein (p.Pro672Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs200805909, ExAC 0.02%). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	Benign	0.11
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	24
Dann	Benign	0.95
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.9	D;.;.;.;.;D;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.0060	D;.;.;.;.;D;.
Sift4G	Benign	0.23	T;T;.;.;.;T;.
Polyphen		0.070	.;B;.;.;B;.;.
Vest4		0.47
MVP		0.78
MPC		0.14
ClinPred		0.54	D
GERP RS		5.7
Varity_R		0.19
gMVP		0.23

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: rs200805909; hg19: chr2-167138246;