2-166288485-T-C

Variant names:

• chr2-166288485-T-C
• rs13402180
• NM_001365536.1:c.1266A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001365536.1(SCN9A):​c.1266A>G​(p.Glu422Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,606,194 control chromosomes in the GnomAD database, including 121,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11102 hom., cov: 31)
  • Exomes 𝑓: 0.39 (110372 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 2.06
• Publications: 20 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-166288485-T-C is Benign according to our data. Variant chr2-166288485-T-C is described in ClinVar as Benign. ClinVar VariationId is 130256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.399 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.1266A>G	p.Glu422Glu	synonymous	Exon 10 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.1266A>G	p.Glu422Glu	synonymous	Exon 10 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1030-6080T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1266A>G	p.Glu422Glu	synonymous	Exon 10 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.1266A>G	p.Glu422Glu	synonymous	Exon 10 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.1266A>G	p.Glu422Glu	synonymous	Exon 10 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57827 AN: 151752 Hom.: 11106 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.367 AC: 91314 AN: 248628 AF XY: 0.368

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.386 AC: 561984 AN: 1454324 Hom.: 110372 Cov.: 35 AF XY: 0.385 AC XY: 279002 AN XY: 723768

African (AFR) AF: 0.377 AC: 12573 AN: 33336

American (AMR) AF: 0.281 AC: 12551 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9264 AN: 26064

East Asian (EAS) AF: 0.307 AC: 12151 AN: 39644

South Asian (SAS) AF: 0.358 AC: 30755 AN: 85950

European-Finnish (FIN) AF: 0.418 AC: 22275 AN: 53352

Middle Eastern (MID) AF: 0.307 AC: 1763 AN: 5746

European-Non Finnish (NFE) AF: 0.396 AC: 437877 AN: 1105444

Other (OTH) AF: 0.379 AC: 22775 AN: 60116

GnomAD4 genome AF: 0.381 AC: 57848 AN: 151870 Hom.: 11102 Cov.: 31 AF XY: 0.377 AC XY: 28010 AN XY: 74200

African (AFR) AF: 0.379 AC: 15701 AN: 41414

American (AMR) AF: 0.319 AC: 4857 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1238 AN: 3470

East Asian (EAS) AF: 0.311 AC: 1601 AN: 5152

South Asian (SAS) AF: 0.357 AC: 1721 AN: 4824

European-Finnish (FIN) AF: 0.413 AC: 4349 AN: 10522

Middle Eastern (MID) AF: 0.253 AC: 74 AN: 292

European-Non Finnish (NFE) AF: 0.403 AC: 27373 AN: 67934

Other (OTH) AF: 0.368 AC: 774 AN: 2104

Alfa AF: 0.389 Hom.: 22920

Bravo AF: 0.372

Asia WGS AF: 0.352 AC: 1231 AN: 3476

EpiCase AF: 0.397

EpiControl AF: 0.384

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (2)
-	-	2	Paroxysmal extreme pain disorder (2)
-	-	2	Primary erythromelalgia (2)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Inherited Erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs13402180; hg19: chr2-167144995; COSMIC: COSV57621333; COSMIC: COSV57621333;