rs9646771

Variant names:

• chr2-166306533-T-C
• rs9646771
• NM_001365536.1:c.444A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-166306533-T-C
• chr2-166306533-T-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.444A>G​(p.Pro148Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,569,836 control chromosomes in the GnomAD database, including 340,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37218 hom., cov: 32)
  • Exomes 𝑓: 0.65 (302882 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.331
• Publications: 25 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=-0.53).
• BP6: Variant 2-166306533-T-C is Benign according to our data. Variant chr2-166306533-T-C is described in ClinVar as Benign. ClinVar VariationId is 130269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.331 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.83 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.444A>G	p.Pro148Pro	synonymous	Exon 4 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.444A>G	p.Pro148Pro	synonymous	Exon 4 of 27	NP_002968.2	Q15858-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.444A>G	p.Pro148Pro	synonymous	Exon 4 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.444A>G	p.Pro148Pro	synonymous	Exon 4 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.444A>G	p.Pro148Pro	synonymous	Exon 4 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105033 AN: 151848 Hom.: 37173 Cov.: 32

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.686

GnomAD2 exomes AF: 0.628 AC: 126287 AN: 201130 AF XY: 0.622

Gnomad AFR exome AF: 0.837

Gnomad AMR exome AF: 0.643

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.625

GnomAD4 exome AF: 0.651 AC: 923173 AN: 1417870 Hom.: 302882 Cov.: 30 AF XY: 0.649 AC XY: 455551 AN XY: 702288

African (AFR) AF: 0.840 AC: 27583 AN: 32852

American (AMR) AF: 0.642 AC: 25400 AN: 39576

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 13993 AN: 25490

East Asian (EAS) AF: 0.467 AC: 18034 AN: 38640

South Asian (SAS) AF: 0.590 AC: 48045 AN: 81448

European-Finnish (FIN) AF: 0.606 AC: 31175 AN: 51410

Middle Eastern (MID) AF: 0.586 AC: 3342 AN: 5704

European-Non Finnish (NFE) AF: 0.662 AC: 717670 AN: 1084002

Other (OTH) AF: 0.646 AC: 37931 AN: 58748

GnomAD4 genome AF: 0.692 AC: 105128 AN: 151966 Hom.: 37218 Cov.: 32 AF XY: 0.685 AC XY: 50872 AN XY: 74256

African (AFR) AF: 0.837 AC: 34738 AN: 41490

American (AMR) AF: 0.657 AC: 10032 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1880 AN: 3472

East Asian (EAS) AF: 0.440 AC: 2264 AN: 5150

South Asian (SAS) AF: 0.582 AC: 2804 AN: 4814

European-Finnish (FIN) AF: 0.606 AC: 6407 AN: 10564

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44704 AN: 67908

Other (OTH) AF: 0.680 AC: 1430 AN: 2102

Alfa AF: 0.668 Hom.: 107620

Bravo AF: 0.699

Asia WGS AF: 0.534 AC: 1859 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	-0.53
CADD	Benign	3.2
DANN	Benign	0.46
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9646771; hg19: chr2-167163043; COSMIC: COSV57602317; COSMIC: COSV57602317;