rs201243874

Variant names:

• chr2-166311552-C-A
• rs201243874
• NM_001365536.1:c.205G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166311552-C-A
• chr2-166311552-C-G
• chr2-166311552-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001365536.1(SCN9A):​c.205G>T​(p.Gly69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,448 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. G69S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 4 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.205G>T	p.Gly69Cys	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.205G>T	p.Gly69Cys	missense_variant	Exon 2 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.205G>T	p.Gly69Cys	missense_variant	Exon 2 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.205G>T	p.Gly69Cys	missense_variant	Exon 2 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.205G>T	p.Gly69Cys	missense_variant	Exon 2 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.205G>T	p.Gly69Cys	missense_variant	Exon 2 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.205G>T	p.Gly69Cys	missense_variant	Exon 3 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151356 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461092 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726900

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111522

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151356 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 73850

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

African (AFR) AF: 0.00 AC: 0 AN: 41170

American (AMR) AF: 0.00 AC: 0 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67878

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;D;.;.;D;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.1	M;M;M;.;M;M;.;.
PhyloP100		1.7
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.6	D;D;.;.;.;D;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D;D;.;.;.;D;.;.
Sift4G	Uncertain	0.010	D;D;.;.;.;D;.;.
Vest4		0.44
MutPred		0.62		Loss of disorder (P = 0.0468);Loss of disorder (P = 0.0468);Loss of disorder (P = 0.0468);Loss of disorder (P = 0.0468);Loss of disorder (P = 0.0468);Loss of disorder (P = 0.0468);Loss of disorder (P = 0.0468);Loss of disorder (P = 0.0468);
MVP		0.81
MPC		0.57
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.48
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs201243874; hg19: chr2-167168062;