NM_006517.5:c.538G>T

Variant names:

• chrX-74521097-G-T
• rs759933264
• NM_006517.5:c.538G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006517.5(SLC16A2):​c.538G>T​(p.Val180Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V180I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC16A2 NM_006517.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.489
• Publications: 0 publications found

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]

SLC16A2 Gene-Disease associations (from GenCC):

• Allan-Herndon-Dudley syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006517.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	NM_006517.5	MANE Select	c.538G>T	p.Val180Phe	missense	Exon 2 of 6	NP_006508.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	ENST00000587091.6	TSL:1 MANE Select	c.538G>T	p.Val180Phe	missense	Exon 2 of 6	ENSP00000465734.1
	SLC16A2	ENST00000636771.1	TSL:5	n.*239G>T		non_coding_transcript_exon	Exon 3 of 7	ENSP00000490445.1
	SLC16A2	ENST00000636771.1	TSL:5	n.*239G>T		3_prime_UTR	Exon 3 of 7	ENSP00000490445.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.760G>T (p.V254F) alteration is located in exon 2 (coding exon 2) of the SLC16A2 gene. This alteration results from a G to T substitution at nucleotide position 760, causing the valine (V) at amino acid position 254 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.49
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.80	P
Vest4		0.63
MutPred		0.57		Loss of glycosylation at T175 (P = 0.2735)
MVP		0.33
MPC		1.9
ClinPred		0.84	D
GERP RS		0.90
PromoterAI		-0.0076	Neutral
Varity_R		0.14
gMVP		0.90
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs759933264; hg19: chrX-73740932;