2-166280510-C-A

Variant names:

• chr2-166280510-C-A
• rs202055175
• NM_001365536.1:c.2190G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001365536.1(SCN9A):​c.2190G>T​(p.Trp730Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,080 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W730L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2190G>T	p.Trp730Cys	missense_variant	Exon 14 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2190G>T	p.Trp730Cys	missense_variant	Exon 14 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2190G>T	p.Trp730Cys	missense_variant	Exon 14 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2157G>T	p.Trp719Cys	missense_variant	Exon 14 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2157G>T	p.Trp719Cys	missense_variant	Exon 14 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2157G>T	p.Trp719Cys	missense_variant	Exon 14 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437080 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712278

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33164

American (AMR) AF: 0.00 AC: 0 AN: 41682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25534

East Asian (EAS) AF: 0.00 AC: 0 AN: 39092

South Asian (SAS) AF: 0.00 AC: 0 AN: 82798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1097710

Other (OTH) AF: 0.00 AC: 0 AN: 59438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;D;.;.;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;H;.;.;H;H;.
PhyloP100		7.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-13	D;.;.;.;.;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;D;.
Vest4		0.94
MutPred		0.61		Loss of MoRF binding (P = 0.018);.;Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);.;.;Loss of MoRF binding (P = 0.018);
MVP		0.84
MPC		0.70
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.60
gMVP		0.66
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs202055175; hg19: chr2-167137020;