2-166286613-G-T

Variant names:

• chr2-166286613-G-T
• rs773066209
• NM_001365536.1:c.1325C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.1325C>A​(p.Ala442Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000359 in 1,393,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A442A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.294

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10741344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1325C>A	p.Ala442Glu	missense_variant	Exon 11 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1325C>A	p.Ala442Glu	missense_variant	Exon 11 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1325C>A	p.Ala442Glu	missense_variant	Exon 11 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1325C>A	p.Ala442Glu	missense_variant	Exon 11 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1325C>A	p.Ala442Glu	missense_variant	Exon 11 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1325C>A	p.Ala442Glu	missense_variant	Exon 11 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000115 AC: 2 AN: 173316 Hom.: 0 AF XY: 0.0000216 AC XY: 2 AN XY: 92658

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: 0.000108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1393388 Hom.: 0 Cov.: 31 AF XY: 0.00000582 AC XY: 4 AN XY: 687558

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: 0.0000674

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000166 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	4.1
DANN	Benign	0.77
DEOGEN2	Benign	0.34	.;T;.;.;T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.61	T;.;T;T;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	1.6	L;L;L;.;L;L;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.5	D;D;.;.;.;D;.
REVEL	Uncertain	0.31
Sift	Benign	0.073	T;D;.;.;.;T;.
Sift4G	Benign	0.24	T;T;.;.;.;T;.
Polyphen		0.0010	.;B;.;.;B;.;.
Vest4		0.19
MVP		0.73
MPC		0.14
ClinPred		0.046	T
GERP RS		0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs773066209; hg19: chr2-167143123;