2-166280610-C-T

Variant names:

• chr2-166280610-C-T
• rs4525717
• NM_001365536.1:c.2105-15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.2105-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,450,794 control chromosomes in the GnomAD database, including 15,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1598 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13855 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.142
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-166280610-C-T is Benign according to our data. Variant chr2-166280610-C-T is described in ClinVar as Benign. ClinVar VariationId is 167660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.2105-15G>A		intron	N/A	NP_001352465.1
	SCN9A	NM_002977.4		c.2072-15G>A		intron	N/A	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1029+3363C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.2105-15G>A		intron	N/A	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.2105-15G>A		intron	N/A	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.2072-15G>A		intron	N/A	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20518 AN: 152030 Hom.: 1600 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.156 AC: 24834 AN: 159548 AF XY: 0.159

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0965

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.139 AC: 180127 AN: 1298646 Hom.: 13855 Cov.: 19 AF XY: 0.140 AC XY: 90339 AN XY: 645746

African (AFR) AF: 0.108 AC: 3170 AN: 29360

American (AMR) AF: 0.0973 AC: 3415 AN: 35108

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3276 AN: 23994

East Asian (EAS) AF: 0.356 AC: 12892 AN: 36222

South Asian (SAS) AF: 0.188 AC: 14352 AN: 76292

European-Finnish (FIN) AF: 0.177 AC: 8683 AN: 49146

Middle Eastern (MID) AF: 0.136 AC: 742 AN: 5460

European-Non Finnish (NFE) AF: 0.127 AC: 125888 AN: 988462

Other (OTH) AF: 0.141 AC: 7709 AN: 54602

GnomAD4 genome AF: 0.135 AC: 20518 AN: 152148 Hom.: 1598 Cov.: 32 AF XY: 0.139 AC XY: 10320 AN XY: 74396

African (AFR) AF: 0.114 AC: 4726 AN: 41518

American (AMR) AF: 0.105 AC: 1597 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3468

East Asian (EAS) AF: 0.358 AC: 1852 AN: 5170

South Asian (SAS) AF: 0.205 AC: 991 AN: 4828

European-Finnish (FIN) AF: 0.181 AC: 1911 AN: 10584

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8518 AN: 67984

Other (OTH) AF: 0.125 AC: 264 AN: 2112

Alfa AF: 0.124 Hom.: 260

Bravo AF: 0.129

Asia WGS AF: 0.254 AC: 882 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	Inherited Erythromelalgia (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.14
DANN	Benign	0.58
PhyloP100		-0.14
Mutation Taster		=100/0	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: rs4525717; hg19: chr2-167137120; COSMIC: COSV57619236; COSMIC: COSV57619236;