rs144755294

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000587091.6(SLC16A2):​c.949C>T​(p.Arg317Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,209,889 control chromosomes in the GnomAD database, including 2 homozygotes. There are 96 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., 56 hem., cov: 22)
Exomes 𝑓: 0.00017 ( 1 hom. 40 hem. )

Consequence

SLC16A2
ENST00000587091.6 missense

Scores

4
4
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.13
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.01689151).
BP6
Variant X-74524732-C-T is Benign according to our data. Variant chrX-74524732-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212187.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}. Variant chrX-74524732-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00153 (171/111749) while in subpopulation AFR AF= 0.00459 (141/30733). AF 95% confidence interval is 0.00397. There are 1 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 56 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC16A2NM_006517.5 linkuse as main transcriptc.949C>T p.Arg317Cys missense_variant 3/6 ENST00000587091.6 NP_006508.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC16A2ENST00000587091.6 linkuse as main transcriptc.949C>T p.Arg317Cys missense_variant 3/61 NM_006517.5 ENSP00000465734 P1
SLC16A2ENST00000590447.1 linkuse as main transcriptc.391C>T p.Arg131Cys missense_variant 2/45 ENSP00000466213
SLC16A2ENST00000636771.1 linkuse as main transcriptc.*650C>T 3_prime_UTR_variant, NMD_transcript_variant 4/75 ENSP00000490445

Frequencies

GnomAD3 genomes
AF:
0.00153
AC:
171
AN:
111697
Hom.:
1
Cov.:
22
AF XY:
0.00165
AC XY:
56
AN XY:
33875
show subpopulations
Gnomad AFR
AF:
0.00457
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00247
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000377
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000753
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000328
AC:
60
AN:
183191
Hom.:
0
AF XY:
0.000148
AC XY:
10
AN XY:
67661
show subpopulations
Gnomad AFR exome
AF:
0.00395
Gnomad AMR exome
AF:
0.000182
Gnomad ASJ exome
AF:
0.000134
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000122
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.000167
AC:
183
AN:
1098140
Hom.:
1
Cov.:
33
AF XY:
0.000110
AC XY:
40
AN XY:
363502
show subpopulations
Gnomad4 AFR exome
AF:
0.00428
Gnomad4 AMR exome
AF:
0.000483
Gnomad4 ASJ exome
AF:
0.0000516
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000309
Gnomad4 OTH exome
AF:
0.000542
GnomAD4 genome
AF:
0.00153
AC:
171
AN:
111749
Hom.:
1
Cov.:
22
AF XY:
0.00165
AC XY:
56
AN XY:
33937
show subpopulations
Gnomad4 AFR
AF:
0.00459
Gnomad4 AMR
AF:
0.00247
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000753
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000180
Hom.:
8
Bravo
AF:
0.00212
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00469
AC:
18
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.000404
AC:
49
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 08, 2014- -
Spastic paraplegia Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 30, 2023- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 29, 2018This 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
Benign, criteria provided, single submitterclinical testingGeneDxApr 06, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.36
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.80
D
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.39
D
MetaRNN
Benign
0.017
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.0
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.61
T
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.49
MVP
0.92
MPC
2.2
ClinPred
0.058
T
GERP RS
4.6
Varity_R
0.49
gMVP
0.70

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.

Other links and lift over

dbSNP: rs144755294; hg19: chrX-73744567; API