chr2-166311628-A-G

Variant names:

• chr2-166311628-A-G
• rs200826539
• NM_001365536.1:c.129T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The ENST00000454569.6(SCN9A):​c.129T>C​(p.Asp43Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,613,138 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: SCN9A ENST00000454569.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -3.88
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-166311628-A-G is Benign according to our data. Variant chr2-166311628-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 332001.
• BP7: Synonymous conserved (PhyloP=-3.88 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000454569.6. 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.129T>C	p.Asp43Asp	synonymous	Exon 2 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.129T>C	p.Asp43Asp	synonymous	Exon 2 of 27	NP_002968.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.129T>C	p.Asp43Asp	synonymous	Exon 2 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.129T>C	p.Asp43Asp	synonymous	Exon 2 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.129T>C	p.Asp43Asp	synonymous	Exon 2 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151482 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000728

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000393 AC: 98 AN: 249312 AF XY: 0.000436

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000389

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000387 AC: 566 AN: 1461656 Hom.: 3 Cov.: 33 AF XY: 0.000446 AC XY: 324 AN XY: 727106

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00112 AC: 97 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53400

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000371 AC: 412 AN: 1111826

Other (OTH) AF: 0.000480 AC: 29 AN: 60372

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151482 Hom.: 0 Cov.: 30 AF XY: 0.000189 AC XY: 14 AN XY: 73960

African (AFR) AF: 0.0000728 AC: 3 AN: 41202

American (AMR) AF: 0.000132 AC: 2 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000322 Hom.: 0

EpiCase AF: 0.000327

EpiControl AF: 0.000534

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	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	Inborn genetic diseases (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)
-	-	1	SCN9A-related disorder (1)
-	-	1	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.089
DANN	Benign	0.38
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism

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: rs200826539; hg19: chr2-167168138;