chr2-166284698-T-C

Variant names:

• chr2-166284698-T-C
• rs201137237
• NM_001365536.1:c.1729A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001365536.1(SCN9A):​c.1729A>G​(p.Ile577Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I577I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.67
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33479124).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.1729A>G	p.Ile577Val	missense	Exon 12 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.1729A>G	p.Ile577Val	missense	Exon 12 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1029+7451T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1729A>G	p.Ile577Val	missense	Exon 12 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.1729A>G	p.Ile577Val	missense	Exon 12 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.1729A>G	p.Ile577Val	missense	Exon 12 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111858

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.010
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.28	N
PhyloP100		7.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.70	N
REVEL	Uncertain	0.30
Sift	Benign	0.080	T
Sift4G	Benign	1.0	T
Polyphen		0.41	B
Vest4		0.37
MVP		0.54
MPC		0.21
ClinPred		0.60	D
GERP RS		5.6
Varity_R		0.063
gMVP		0.59
Mutation Taster		=6/94	disease causing

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: rs201137237; hg19: chr2-167141208; COSMIC: COSV57612486; COSMIC: COSV57612486;