rs606231279

Variant names:

• chr2-166228871-C-AA
• rs606231279
• NM_001365536.1:c.4026delGinsTT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001365536.1(SCN9A):​c.4026delGinsTT​(p.Leu1342PhefsTer8) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1342V) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 frameshift, missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:2 U:1
• Conservation: PhyloP100: 1.37
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166228871-C-AA is Pathogenic according to our data. Variant chr2-166228871-C-AA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157598.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4026delGinsTT	p.Leu1342PhefsTer8	frameshift_variant, missense_variant	Exon 22 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4026delGinsTT	p.Leu1342PhefsTer8	frameshift_variant, missense_variant	Exon 22 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.4026delGinsTT	p.Leu1342PhefsTer8	frameshift_variant, missense_variant	Exon 22 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3993delGinsTT	p.Leu1331PhefsTer8	frameshift_variant, missense_variant	Exon 22 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3993delGinsTT	p.Leu1331PhefsTer8	frameshift_variant, missense_variant	Exon 22 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Pathogenic:1

Nov 16, 2021

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Neuropathy, hereditary sensory and autonomic, type IId Pathogenic:1

Apr 30, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs606231279; hg19: chr2-167085381;