rs201569378

Positions:

• chr2-166284752-C-G
• chr2-166284752-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001365536.1(SCN9A):​c.1675G>C​(p.Gly559Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 6.8e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.87

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1675G>C	p.Gly559Arg	missense_variant	12/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1675G>C	p.Gly559Arg	missense_variant	12/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1675G>C	p.Gly559Arg	missense_variant	12/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1675G>C	p.Gly559Arg	missense_variant	12/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1675G>C	p.Gly559Arg	missense_variant	12/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1675G>C	p.Gly559Arg	missense_variant	12/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461584 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	.;D;.;.;D;.;.
Eigen	Benign	-0.038
Eigen_PC	Benign	0.0095
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;.;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.3	M;M;M;.;M;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.7	D;.;.;.;.;D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.020	D;.;.;.;.;D;.
Sift4G	Benign	0.088	T;T;.;.;.;T;.
Polyphen		0.38	.;B;.;.;B;.;.
Vest4		0.62
MVP		0.79
MPC		0.18
ClinPred		0.84	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.63

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: rs201569378; hg19: chr2-167141262;