2-166198890-TGTA-AGTT

Position:

• chr2-166198890-TGTA-AGTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365536.1(SCN9A):​c.5746_5749delTACAinsAACT​(p.TyrIle1916AsnLeu) variant causes a 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.5746_5749delTACAinsAACT	p.TyrIle1916AsnLeu	missense_variant		ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.5746_5749delTACAinsAACT	p.TyrIle1916AsnLeu	missense_variant			NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.5746_5749delTACAinsAACT	p.TyrIle1916AsnLeu	missense_variant		5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.5713_5716delTACAinsAACT	p.TyrIle1905AsnLeu	missense_variant		5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.5713_5716delTACAinsAACT	p.TyrIle1905AsnLeu	missense_variant				ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2019

In summary, this variant is a rare in-frame deletion and insertion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted and inserted amino acids is currently unknown. This variant is reported as two separate single-nucleotide changes in population databases (c.5713T>A, ExAC 0.002% and c.5716A>T, ExAC 0.002%). In all reads displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.5713_5716delinsAACT). However, this frequency data may be unreliable, as metrics indicate poor quality at position c.5716 in the ExAC database. This variant has not been reported in the literature in individuals with a SCN9A-related disease. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN9A-related disease. This sequence change deletes and inserts 4 nucleotides in exon 27 of the SCN9A mRNA (c.5713_5716delinsAACT). This leads to a deletion and insertion of 2 amino acid residues in the SCN9A protein (p.Tyr1905_Ile1906delinsAsnLeu) but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553472800; hg19: chr2-167055400;