X-74421902-G-C

Position:

chrX-74421902-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006517.5(SLC16A2):c.265G>C(p.Ala89Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000612 in 1,209,393 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts 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. A89T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., 10 hem., cov: 24)

Exomes 𝑓: 0.000037 ( 0 hom. 9 hem. )

Consequence

SLC16A2
NM_006517.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.863

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035247743).

BP6

Variant X-74421902-G-C is Benign according to our data. Variant chrX-74421902-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 240686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000292 (33/113004) while in subpopulation AFR AF= 0.000993 (31/31208). AF 95% confidence interval is 0.000719. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC16A2	NM_006517.5 linkuse as main transcript	c.265G>C	p.Ala89Pro	missense_variant	1/6	ENST00000587091.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC16A2	ENST00000587091.6 linkuse as main transcript	c.265G>C	p.Ala89Pro	missense_variant	1/6	1	NM_006517.5	P1
SLC16A2	ENST00000636771.1 linkuse as main transcript	c.13G>C	p.Ala5Pro	missense_variant, NMD_transcript_variant	1/7	5

Frequencies

GnomAD3 genomes

AF:

0.000292

AC:

AN:

112959

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

AN XY:

35101

show subpopulations

Gnomad AFR

AF:

0.000995

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.000657

GnomAD3 exomes

AF:

0.0000574

AC:

AN:

174251

Hom.:

AF XY:

0.0000317

AC XY:

AN XY:

63087

show subpopulations

Gnomad AFR exome

AF:

0.000753

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.0000374

AC:

AN:

1096389

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

362199

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.000292

AC:

AN:

113004

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

AN XY:

35156

show subpopulations

Gnomad4 AFR

AF:

0.000993

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.000649

Bravo

AF:

0.000302

ESP6500AA

AF:

0.000262

AC:

ESP6500EA

AF:

0.000150

AC:

ExAC

AF:

0.0000825

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.44

M_CAP

Benign

0.0036

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.52

Sift4G

Benign

0.31

Polyphen

0.88

Vest4

0.15

MVP

0.24

MPC

1.1

ClinPred

0.017

GERP RS

1.4

Varity_R

0.14

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over