rs121908920

Variant names:

• chr2-166311573-T-A
• NM_001365536.1:c.184A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166311573-T-A
• chr2-166311573-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001365536.1(SCN9A):​c.184A>T​(p.Ile62Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,626 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. I62V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166311573-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.184A>T	p.Ile62Phe	missense_variant	Exon 2 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.184A>T	p.Ile62Phe	missense_variant	Exon 2 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.184A>T	p.Ile62Phe	missense_variant	Exon 2 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.184A>T	p.Ile62Phe	missense_variant	Exon 2 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.184A>T	p.Ile62Phe	missense_variant	Exon 2 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.184A>T	p.Ile62Phe	missense_variant	Exon 2 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.184A>T	p.Ile62Phe	missense_variant	Exon 3 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461626 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	.;D;.;.;D;.;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M;M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.5	D;D;.;.;.;D;.;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;.;.;.;D;.;.
Sift4G	Benign	0.20	T;T;.;.;.;T;.;.
Vest4		0.55
MutPred		0.68		Loss of stability (P = 0.048);Loss of stability (P = 0.048);Loss of stability (P = 0.048);Loss of stability (P = 0.048);Loss of stability (P = 0.048);Loss of stability (P = 0.048);Loss of stability (P = 0.048);Loss of stability (P = 0.048);
MVP		0.86
MPC		0.70
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.38

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: chr2-167168083;