chr2-166311552-C-G

Position:

• chr2-166311552-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365536.1(SCN9A):​c.205G>C​(p.Gly69Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66

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]

SCN9A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38698483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.205G>C	p.Gly69Arg	missense_variant	2/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.205G>C	p.Gly69Arg	missense_variant	2/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.205G>C	p.Gly69Arg	missense_variant	2/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.205G>C	p.Gly69Arg	missense_variant	2/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.205G>C	p.Gly69Arg	missense_variant	2/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.205G>C	p.Gly69Arg	missense_variant	2/15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.205G>C	p.Gly69Arg	missense_variant	3/11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461092 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726900

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: 0.00000270

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	Benign	0.17
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	.;T;.;.;T;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.81	T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.7	L;L;L;.;L;L;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.6	D;D;.;.;.;D;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.040	D;D;.;.;.;D;.;.
Sift4G	Benign	0.12	T;T;.;.;.;T;.;.
Vest4		0.38
MutPred		0.60		Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);
MVP		0.61
MPC		0.25
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.23
gMVP		0.40

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: rs201243874; hg19: chr2-167168062; COSMIC: COSV100311921;