rs759933264

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006517.5(SLC16A2):c.538G>A(p.Val180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,210,501 control chromosomes in the GnomAD database, including 2 homozygotes. There are 64 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V180F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., 23 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 1 hom. 41 hem. )

Consequence

SLC16A2
NM_006517.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.489

Publications

2 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010031223).

BP6

Variant X-74521097-G-A is Benign according to our data. Variant chrX-74521097-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 458241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000481 (54/112341) while in subpopulation AMR AF = 0.00432 (46/10636). AF 95% confidence interval is 0.00333. There are 1 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A2	NM_006517.5 link	c.538G>A	p.Val180Ile	missense_variant	Exon 2 of 6	ENST00000587091.6	NP_006508.2	P36021

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC16A2	ENST00000587091.6 link	c.538G>A	p.Val180Ile	missense_variant	Exon 2 of 6	1	NM_006517.5	ENSP00000465734.1	P36021
SLC16A2	ENST00000636771.1 link	n.*239G>A		non_coding_transcript_exon_variant	Exon 3 of 7	5		ENSP00000490445.1	A0A1B0GVB4
SLC16A2	ENST00000636771.1 link	n.*239G>A		3_prime_UTR_variant	Exon 3 of 7	5		ENSP00000490445.1	A0A1B0GVB4
SLC16A2	ENST00000590447.1 link	c.-24G>A		upstream_gene_variant		5		ENSP00000466213.1	K7ELT4

Frequencies

GnomAD3 genomes

AF:

0.000481

AC:

AN:

112289

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00433

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.000369

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00133

GnomAD2 exomes

AF:

0.000327

AC:

AN:

183483

AF XY:

0.000280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

AF:

0.000114

AC:

125

AN:

1098160

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

363514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00170

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.000166

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000594

AC:

AN:

842058

Other (OTH)

AF:

0.000152

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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

AF:

0.000481

AC:

AN:

112341

Hom.:

Cov.:

AF XY:

0.000667

AC XY:

AN XY:

34503

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30923

American (AMR)

AF:

0.00432

AC:

AN:

10636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.000280

AC:

AN:

3569

South Asian (SAS)

AF:

0.000370

AC:

AN:

2702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

53266

Other (OTH)

AF:

0.00131

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0000681

Hom.:

Bravo

AF:

0.000688

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 15, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Allan-Herndon-Dudley syndrome

Benign:1

Jun 21, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.6

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.18

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.83

M_CAP

Benign

0.0067

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.035

PhyloP100

0.49

PrimateAI

Benign

0.33

Sift4G

Benign

0.75

Polyphen

0.032

Vest4

0.068

MutPred

0.55

Loss of catalytic residue at V180 (P = 0.2057);

MVP

0.068

MPC

0.72

ClinPred

0.0081

GERP RS

0.90

PromoterAI

0.083

Neutral

(source)

Varity_R

0.041

gMVP

0.27

Mutation Taster

=96/4

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over