9-89325525-CT-C

Position:

• chr9-89325525-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024077.5(SECISBP2):​c.283delT​(p.Tyr95fs) variant causes a frameshift 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SECISBP2 NM_024077.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.107

Genes affected

SECISBP2 (HGNC:30972): (SECIS binding protein 2) The protein encoded by this gene is one of the essential components of the machinery involved in co-translational insertion of selenocysteine (Sec) into selenoproteins. Sec is encoded by the UGA codon, which normally signals translation termination. The recoding of UGA as Sec codon requires a Sec insertion sequence (SECIS) element; present in the 3' untranslated regions of eukaryotic selenoprotein mRNAs. This protein specifically binds to the SECIS element, which is stimulated by a Sec-specific translation elongation factor. Mutations in this gene have been associated with reduction in enzymatic activity of type II iodothyronine deiodinase (a selenoprotein) and abnormal thyroid hormone metabolism. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

SECISBP2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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 9-89325525-CT-C is Pathogenic according to our data. Variant chr9-89325525-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 452803.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SECISBP2	NM_024077.5	c.283delT	p.Tyr95fs	frameshift_variant	3/17	ENST00000375807.8	NP_076982.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SECISBP2	ENST00000375807.8	c.283delT	p.Tyr95fs	frameshift_variant	3/17	1	NM_024077.5	ENSP00000364965.3
SECISBP2	ENST00000339901.8	c.85-21delT		intron_variant		1		ENSP00000364959.3
SECISBP2	ENST00000470305.1	n.3328delT		non_coding_transcript_exon_variant	1/3	1
SECISBP2	ENST00000534113.6	c.79delT	p.Tyr27fs	frameshift_variant	3/17	2		ENSP00000436650.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2017

The c.283delT variant in the SECISBP2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.283delT variant causes a frameshift starting with codon Tyrosine 95, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 31 of the new reading frame, denoted p.Tyr95IlefsX31. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.283delT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.283delT as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554716257; hg19: chr9-91940440;