2-166304225-A-G

Variant names:

• chr2-166304225-A-G
• rs74449889
• NM_001365536.1:c.688+13T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.688+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,612,160 control chromosomes in the GnomAD database, including 2,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (223 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1869 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.727
• Publications: 5 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).
• BP6: Variant 2-166304225-A-G is Benign according to our data. Variant chr2-166304225-A-G is described in ClinVar as Benign. ClinVar VariationId is 139076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

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.688+13T>C		intron	N/A	NP_001352465.1
	SCN9A	NM_002977.4		c.688+13T>C		intron	N/A	NP_002968.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.688+13T>C		intron	N/A	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.688+13T>C		intron	N/A	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.688+13T>C		intron	N/A	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3257 AN: 152090 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.0248

GnomAD2 exomes AF: 0.0486 AC: 12134 AN: 249452 AF XY: 0.0396

Gnomad AFR exome AF: 0.00379

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.00766

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.0348

GnomAD4 exome AF: 0.0153 AC: 22366 AN: 1459950 Hom.: 1869 Cov.: 31 AF XY: 0.0143 AC XY: 10387 AN XY: 726370

African (AFR) AF: 0.00272 AC: 91 AN: 33436

American (AMR) AF: 0.224 AC: 9974 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00739 AC: 193 AN: 26112

East Asian (EAS) AF: 0.154 AC: 6124 AN: 39664

South Asian (SAS) AF: 0.0158 AC: 1366 AN: 86208

European-Finnish (FIN) AF: 0.00811 AC: 433 AN: 53378

Middle Eastern (MID) AF: 0.00469 AC: 27 AN: 5762

European-Non Finnish (NFE) AF: 0.00282 AC: 3129 AN: 1110498

Other (OTH) AF: 0.0171 AC: 1029 AN: 60330

GnomAD4 genome AF: 0.0215 AC: 3267 AN: 152210 Hom.: 223 Cov.: 32 AF XY: 0.0243 AC XY: 1812 AN XY: 74432

African (AFR) AF: 0.00363 AC: 151 AN: 41572

American (AMR) AF: 0.121 AC: 1854 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.133 AC: 685 AN: 5160

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4822

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00413 AC: 281 AN: 67980

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.00962 Hom.: 29

Bravo AF: 0.0316

Asia WGS AF: 0.0670 AC: 234 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	not provided (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)
-	-	1	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.83
PhyloP100		0.73
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74449889; hg19: chr2-167160735; COSMIC: COSV57611217; COSMIC: COSV57611217;