rs201709980

Variant names:

• chr2-166280571-C-A
• NM_001365536.1:c.2129G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166280571-C-A
• chr2-166280571-C-T

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.2129G>T​(p.Cys710Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,430,662 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 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: 0.0000014 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2129G>T	p.Cys710Phe	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.2129G>T	p.Cys710Phe	missense_variant	Exon 14 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2129G>T	p.Cys710Phe	missense_variant	Exon 14 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2096G>T	p.Cys699Phe	missense_variant	Exon 14 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2096G>T	p.Cys699Phe	missense_variant	Exon 14 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2096G>T	p.Cys699Phe	missense_variant	Exon 14 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430662 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708538

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: 0.0000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	.;D;.;.;D;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H;.;.;H;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-10	D;.;.;.;.;D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Uncertain	0.018	D;D;.;.;.;D;.
Vest4		0.94
MutPred		0.57		Gain of MoRF binding (P = 0.0731);.;Gain of MoRF binding (P = 0.0731);Gain of MoRF binding (P = 0.0731);.;.;Gain of MoRF binding (P = 0.0731);
MVP		0.96
MPC		0.69
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-167137081;