rs6747673

Variant names:

• chr2-166288464-A-T
• rs6747673
• NM_001365536.1:c.1287T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365536.1(SCN9A):​c.1287T>A​(p.Arg429Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,601,758 control chromosomes in the GnomAD database, including 195,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24861 hom., cov: 31)
  • Exomes 𝑓: 0.48 (170462 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.447
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-166288464-A-T is Benign according to our data. Variant chr2-166288464-A-T is described in ClinVar as Benign. ClinVar VariationId is 130257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.447 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 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.1287T>A	p.Arg429Arg	synonymous	Exon 10 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.1287T>A	p.Arg429Arg	synonymous	Exon 10 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1030-6101A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1287T>A	p.Arg429Arg	synonymous	Exon 10 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.1287T>A	p.Arg429Arg	synonymous	Exon 10 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.1287T>A	p.Arg429Arg	synonymous	Exon 10 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84583 AN: 151694 Hom.: 24822 Cov.: 31

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.548

GnomAD2 exomes AF: 0.493 AC: 122267 AN: 247868 AF XY: 0.484

Gnomad AFR exome AF: 0.761

Gnomad AMR exome AF: 0.540

Gnomad ASJ exome AF: 0.504

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.487

GnomAD4 exome AF: 0.480 AC: 696049 AN: 1449946 Hom.: 170462 Cov.: 33 AF XY: 0.478 AC XY: 344784 AN XY: 721474

African (AFR) AF: 0.766 AC: 25517 AN: 33324

American (AMR) AF: 0.534 AC: 23784 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 13111 AN: 26008

East Asian (EAS) AF: 0.384 AC: 15229 AN: 39610

South Asian (SAS) AF: 0.441 AC: 37570 AN: 85280

European-Finnish (FIN) AF: 0.484 AC: 25774 AN: 53254

Middle Eastern (MID) AF: 0.457 AC: 2607 AN: 5708

European-Non Finnish (NFE) AF: 0.475 AC: 523042 AN: 1102270

Other (OTH) AF: 0.491 AC: 29415 AN: 59926

GnomAD4 genome AF: 0.558 AC: 84685 AN: 151812 Hom.: 24861 Cov.: 31 AF XY: 0.553 AC XY: 41008 AN XY: 74194

African (AFR) AF: 0.753 AC: 31202 AN: 41412

American (AMR) AF: 0.526 AC: 7996 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1731 AN: 3468

East Asian (EAS) AF: 0.381 AC: 1964 AN: 5156

South Asian (SAS) AF: 0.436 AC: 2100 AN: 4816

European-Finnish (FIN) AF: 0.488 AC: 5143 AN: 10530

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 32974 AN: 67906

Other (OTH) AF: 0.546 AC: 1152 AN: 2110

Alfa AF: 0.509 Hom.: 6630

Bravo AF: 0.566

Asia WGS AF: 0.445 AC: 1552 AN: 3476

ClinVar

ClinVar submissions as Germline

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	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.5
DANN	Benign	0.74
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs6747673; hg19: chr2-167144974; COSMIC: COSV57611204; COSMIC: COSV57611204;