chr2-166203939-A-T

Variant names:

• chr2-166203939-A-T
• rs10180721
• NM_001365536.1:c.4774+16T>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.4774+16T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,446,268 control chromosomes in the GnomAD database, including 549,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60405 hom., cov: 33)
  • Exomes 𝑓: 0.87 (489277 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0760
• Publications: 10 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=-0.82).
• BP6: Variant 2-166203939-A-T is Benign according to our data. Variant chr2-166203939-A-T is described in ClinVar as Benign. ClinVar VariationId is 258888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 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.4774+16T>A		intron	N/A	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.4741+16T>A		intron	N/A	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.611+4121A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4774+16T>A		intron	N/A	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.4774+16T>A		intron	N/A	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.4741+16T>A		intron	N/A	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.891 AC: 135255 AN: 151834 Hom.: 60362 Cov.: 33

Gnomad AFR AF: 0.937

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.886

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.951

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.883

GnomAD2 exomes AF: 0.883 AC: 158939 AN: 179950 AF XY: 0.880

Gnomad AFR exome AF: 0.938

Gnomad AMR exome AF: 0.906

Gnomad ASJ exome AF: 0.910

Gnomad EAS exome AF: 0.953

Gnomad FIN exome AF: 0.892

Gnomad NFE exome AF: 0.863

Gnomad OTH exome AF: 0.875

GnomAD4 exome AF: 0.869 AC: 1124794 AN: 1294316 Hom.: 489277 Cov.: 18 AF XY: 0.868 AC XY: 560294 AN XY: 645254

African (AFR) AF: 0.937 AC: 26995 AN: 28816

American (AMR) AF: 0.902 AC: 31594 AN: 35044

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 21483 AN: 23680

East Asian (EAS) AF: 0.949 AC: 35065 AN: 36962

South Asian (SAS) AF: 0.839 AC: 62674 AN: 74736

European-Finnish (FIN) AF: 0.895 AC: 44807 AN: 50082

Middle Eastern (MID) AF: 0.873 AC: 4638 AN: 5314

European-Non Finnish (NFE) AF: 0.863 AC: 849943 AN: 985420

Other (OTH) AF: 0.877 AC: 47595 AN: 54262

GnomAD4 genome AF: 0.891 AC: 135354 AN: 151952 Hom.: 60405 Cov.: 33 AF XY: 0.890 AC XY: 66080 AN XY: 74276

African (AFR) AF: 0.937 AC: 38957 AN: 41558

American (AMR) AF: 0.886 AC: 13508 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 3156 AN: 3468

East Asian (EAS) AF: 0.950 AC: 4923 AN: 5180

South Asian (SAS) AF: 0.830 AC: 3994 AN: 4814

European-Finnish (FIN) AF: 0.888 AC: 9403 AN: 10594

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.863 AC: 58503 AN: 67782

Other (OTH) AF: 0.882 AC: 1860 AN: 2108

Alfa AF: 0.886 Hom.: 10973

Bravo AF: 0.896

Asia WGS AF: 0.886 AC: 3078 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (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	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.3
DANN	Benign	0.80
PhyloP100		-0.076
Mutation Taster		=100/0	polymorphism (auto)

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: rs10180721; hg19: chr2-167060449;