2-166281803-C-T

Variant names:

• chr2-166281803-C-T
• rs200014315
• NM_001365536.1:c.1980G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001365536.1(SCN9A):​c.1980G>A​(p.Thr660Thr) 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 1,600,620 control chromosomes in the GnomAD database, including 1 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 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: -0.337
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-166281803-C-T is Benign according to our data. Variant chr2-166281803-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 331984.
• BP7: Synonymous conserved (PhyloP=-0.337 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.1980G>A	p.Thr660Thr	synonymous	Exon 13 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.1947G>A	p.Thr649Thr	synonymous	Exon 13 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.1029+4556C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1980G>A	p.Thr660Thr	synonymous	Exon 13 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.1980G>A	p.Thr660Thr	synonymous	Exon 13 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.1947G>A	p.Thr649Thr	synonymous	Exon 13 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 35 AN: 150720 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000474

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000353 AC: 82 AN: 232338 AF XY: 0.000381

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000653

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000959

Gnomad NFE exome AF: 0.000716

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000383 AC: 555 AN: 1449782 Hom.: 1 Cov.: 30 AF XY: 0.000384 AC XY: 277 AN XY: 720954

African (AFR) AF: 0.0000614 AC: 2 AN: 32586

American (AMR) AF: 0.0000476 AC: 2 AN: 41998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25560

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39526

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83504

European-Finnish (FIN) AF: 0.0000944 AC: 5 AN: 52980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.000476 AC: 527 AN: 1108102

Other (OTH) AF: 0.000267 AC: 16 AN: 59848

GnomAD4 genome AF: 0.000232 AC: 35 AN: 150838 Hom.: 0 Cov.: 32 AF XY: 0.000217 AC XY: 16 AN XY: 73696

African (AFR) AF: 0.0000728 AC: 3 AN: 41182

American (AMR) AF: 0.00 AC: 0 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000474 AC: 32 AN: 67508

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.000238

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	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	-	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.2
DANN	Benign	0.67
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200014315; hg19: chr2-167138313; COSMIC: COSV57604865; COSMIC: COSV57604865;