chrX-74421639-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006517.5(SLC16A2):​c.2T>G​(p.Met1?) variant causes a start lost 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)

Consequence

SLC16A2
NM_006517.5 start_lost

Scores

3
3
5

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.36
Variant links:
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 12 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-74421639-T-G is Pathogenic according to our data. Variant chrX-74421639-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2024767.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC16A2NM_006517.5 linkuse as main transcriptc.2T>G p.Met1? start_lost 1/6 ENST00000587091.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC16A2ENST00000587091.6 linkuse as main transcriptc.2T>G p.Met1? start_lost 1/61 NM_006517.5 P1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 19, 2022For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SLC16A2 protein in which other variant(s) (p.Ser120Phe, also known as p.Ser194Phe) have been determined to be pathogenic (PMID: 15889350, 25527620, 27977298). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with SLC16A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SLC16A2 mRNA. The next in-frame methionine is located at codon 127. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Benign
-0.50
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.18
T
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Benign
-0.69
T
MutationTaster
Benign
1.0
D;N
Sift4G
Uncertain
0.0030
D
Polyphen
0.65
P
Vest4
0.43
MutPred
0.91
Gain of MoRF binding (P = 0.0014);
MVP
0.47
ClinPred
0.86
D
GERP RS
2.5
Varity_R
0.71
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-73641474; API