dbSNP rs797045964: SLC16A2:p.Thr80Arg (chrX-74421876-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006517.5(SLC16A2):c.239C>G(p.Thr80Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,095,211 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T80M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000046 ( 0 hom. 2 hem. )

Consequence

SLC16A2
NM_006517.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.288

Publications

0 publications found

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]

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)

SLC16A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08797175).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A2	NM_006517.5 link	c.239C>G	p.Thr80Arg	missense_variant	Exon 1 of 6	ENST00000587091.6	NP_006508.2	P36021

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC16A2	ENST00000587091.6 link	c.239C>G	p.Thr80Arg	missense_variant	Exon 1 of 6	1	NM_006517.5	ENSP00000465734.1		P36021
SLC16A2	ENST00000636771.1 link	n.-17C>G		upstream_gene_variant		5		ENSP00000490445.1		A0A1B0GVB4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000586

AC:

AN:

170705

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000457

AC:

AN:

1095211

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

361285

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26362

American (AMR)

AF:

0.00

AC:

AN:

35046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19288

East Asian (EAS)

AF:

0.00

AC:

AN:

30127

South Asian (SAS)

AF:

0.00

AC:

AN:

53693

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40115

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3772

European-Non Finnish (NFE)

AF:

0.00000595

AC:

AN:

840888

Other (OTH)

AF:

0.00

AC:

AN:

45920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.2

PhyloP100

0.29

PrimateAI

Uncertain

0.63

Sift4G

Benign

0.50

Polyphen

0.013

Vest4

0.12

MutPred

0.20

Loss of glycosylation at T80 (P = 7e-04);

MVP

0.22

MPC

1.1

ClinPred

0.070

GERP RS

3.1

PromoterAI

0.25

Neutral

(source)

Varity_R

0.18

gMVP

0.21

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over