X-74524673-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_006517.5(SLC16A2):c.890G>C(p.Arg297Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,080 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 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. R297H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

SLC16A2
NM_006517.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0620

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-74524672-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 449964.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.106316924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A2	NM_006517.5 link	c.890G>C	p.Arg297Pro	missense_variant	Exon 3 of 6	ENST00000587091.6	NP_006508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC16A2	ENST00000587091.6 link	c.890G>C	p.Arg297Pro	missense_variant	Exon 3 of 6	1	NM_006517.5	ENSP00000465734.1
SLC16A2	ENST00000590447.1 link	c.329G>C	p.Arg110Pro	missense_variant	Exon 2 of 4	5		ENSP00000466213.1
SLC16A2	ENST00000636771.1 link	n.*591G>C		non_coding_transcript_exon_variant	Exon 4 of 7	5		ENSP00000490445.1
SLC16A2	ENST00000636771.1 link	n.*591G>C		3_prime_UTR_variant	Exon 4 of 7	5		ENSP00000490445.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098080

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363442

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40469

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842035

Other (OTH)

AF:

0.0000217

AC:

AN:

46094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Feb 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 297 of the SLC16A2 protein (p.Arg297Pro). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC16A2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.4

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.36

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.72

M_CAP

Benign

0.028

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

-0.062

PrimateAI

Benign

0.27

Sift4G

Uncertain

0.024

Vest4

0.13

ClinPred

0.062

GERP RS

-7.7

Varity_R

0.29

gMVP

0.76

Mutation Taster

=85/15

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over