rs1411882430

Variant names:

• chrX-74531496-C-G
• rs1411882430
• NM_006517.5:c.1563C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-74531496-C-G
• chrX-74531496-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006517.5(SLC16A2):​c.1563C>G​(p.Asp521Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 112,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: SLC16A2 NM_006517.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.274

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03582409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A2	NM_006517.5	c.1563C>G	p.Asp521Glu	missense_variant	Exon 6 of 6	ENST00000587091.6	NP_006508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC16A2	ENST00000587091.6	c.1563C>G	p.Asp521Glu	missense_variant	Exon 6 of 6	1	NM_006517.5	ENSP00000465734.1
SLC16A2	ENST00000590447.1	c.*86C>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000466213.1
SLC16A2	ENST00000636771.1	n.*1264C>G		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000490445.1
SLC16A2	ENST00000636771.1	n.*1264C>G		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000490445.1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112194 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34338

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000941

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112194 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000941

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 521 of the SLC16A2 protein (p.Asp521Glu). 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. ClinVar contains an entry for this variant (Variation ID: 521525). 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 with a negative predictive value of 80%. 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. -

Inborn genetic diseases Uncertain:1

Jan 27, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.047
DANN	Benign	0.76
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.60	N
PrimateAI	Benign	0.40	T
Sift4G	Benign	0.82	T
Polyphen		0.0010	B
Vest4		0.043
MutPred		0.15		Loss of helix (P = 0.2662);
MVP		0.068
MPC		0.84
ClinPred		0.070	T
GERP RS		-3.4
Varity_R		0.060
gMVP		0.064

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

Other links and lift over

dbSNP: rs1411882430; hg19: chrX-73751331;