NM_001365536.1:c.684C>G

Variant names:

• chr2-166304242-G-C
• rs71428908
• NM_001365536.1:c.684C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001365536.1(SCN9A):​c.684C>G​(p.Ile228Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,613,092 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I228I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:2
• Conservation: PhyloP100: -1.00
• Publications: 37 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 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001365536.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.093299).

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.684C>G	p.Ile228Met	missense	Exon 6 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.684C>G	p.Ile228Met	missense	Exon 6 of 27	NP_002968.2	Q15858-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.684C>G	p.Ile228Met	missense	Exon 6 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.684C>G	p.Ile228Met	missense	Exon 6 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.684C>G	p.Ile228Met	missense	Exon 6 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000893 AC: 223 AN: 249660 AF XY: 0.000857

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000925

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00123 AC: 1791 AN: 1460884 Hom.: 1 Cov.: 31 AF XY: 0.00119 AC XY: 862 AN XY: 726762

African (AFR) AF: 0.0000598 AC: 2 AN: 33458

American (AMR) AF: 0.000134 AC: 6 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00152 AC: 1691 AN: 1111246

Other (OTH) AF: 0.000679 AC: 41 AN: 60356

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74432

African (AFR) AF: 0.000217 AC: 9 AN: 41540

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000989 Hom.: 1

Bravo AF: 0.000676

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000964 AC: 117

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00149

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	-	not provided (7)
-	2	-	not specified (2)
-	1	1	Primary erythromelalgia (2)
-	1	-	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)
-	1	-	Generalized epilepsy with febrile seizures plus, type 7 (1)
-	1	-	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	1	-	Primary erythromelalgia;C0751122:Severe myoclonic epilepsy in infancy;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive;C2751778:Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	1	-	Primary erythromelalgia;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.093	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-1.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.10	T
Vest4		0.89
MVP		0.72
MPC		0.56
ClinPred		0.15	T
GERP RS		-3.4
Varity_R		0.87
gMVP		0.76
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs71428908; hg19: chr2-167160752;