X-74421662-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006517.5(SLC16A2):c.25G>T(p.Glu9Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
SLC16A2
NM_006517.5 stop_gained
NM_006517.5 stop_gained
Scores
2
1
2
Clinical Significance
Conservation
PhyloP100: 1.33
Genes affected
SLC16A2 (HGNC:10923): (solute carrier family 16 member 2) This gene encodes an integral membrane protein that functions as a transporter of thyroid hormone. The encoded protein facilitates the cellular importation of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and diidothyronine (T2). This gene is expressed in many tissues and likely plays an important role in the development of the central nervous system. Loss of function mutations in this gene are associated with psychomotor retardation in males while females exhibit no neurological defects and more moderate thyroid-deficient phenotypes. This gene is subject to X-chromosome inactivation. Mutations in this gene are the cause of Allan-Herndon-Dudley syndrome. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 77 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-74421662-G-T is Pathogenic according to our data. Variant chrX-74421662-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2706151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC16A2 | NM_006517.5 | c.25G>T | p.Glu9Ter | stop_gained | 1/6 | ENST00000587091.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC16A2 | ENST00000587091.6 | c.25G>T | p.Glu9Ter | stop_gained | 1/6 | 1 | NM_006517.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1089402Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 357678
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1089402
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31
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357678
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GnomAD4 genome Cov.: 23
GnomAD4 genome
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23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | This sequence change creates a premature translational stop signal (p.Glu9*) in the SLC16A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC16A2 are known to be pathogenic (PMID: 20083155, 25527620). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC16A2-related conditions. For these reasons, this variant has been classified as Pathogenic. - |
Allan-Herndon-Dudley syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2024 | Variant summary: SLC16A2 c.25G>T (p.Glu9X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 1089400 control chromosomes (gnomAD v.4.0). c.25G>T has been reported in the literature in a hemizygous individual affected with Allan-Herndon-Dudley Syndrome (Kocaaga_2022). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.