X-74531529-C-T

Variant names:

• chrX-74531529-C-T
• rs199904356
• NM_006517.5:c.1596C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_006517.5(SLC16A2):​c.1596C>T​(p.Ser532Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,207,168 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 313 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 0.00055 (0 hom., 12 hem., cov: 23)
  • Exomes 𝑓: 0.00087 (0 hom. 301 hem.)
• Consequence: SLC16A2 NM_006517.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0880
• Publications: 0 publications found

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: ClinGen, G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant X-74531529-C-T is Benign according to our data. Variant chrX-74531529-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167692.
• BP7: Synonymous conserved (PhyloP=-0.088 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000553 (62/112067) while in subpopulation NFE AF = 0.00094 (50/53166). AF 95% confidence interval is 0.000733. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 12 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006517.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	NM_006517.5	MANE Select	c.1596C>T	p.Ser532Ser	synonymous	Exon 6 of 6	NP_006508.2	P36021

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC16A2	ENST00000587091.6	TSL:1 MANE Select	c.1596C>T	p.Ser532Ser	synonymous	Exon 6 of 6	ENSP00000465734.1	P36021
	SLC16A2	ENST00000878592.1		c.1710C>T	p.Ser570Ser	synonymous	Exon 7 of 7	ENSP00000548651.1
	SLC16A2	ENST00000922847.1		c.1674C>T	p.Ser558Ser	synonymous	Exon 7 of 7	ENSP00000592906.1

Frequencies

GnomAD3 genomes AF: 0.000554 AC: 62 AN: 112011 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000566

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000940

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.000534 AC: 98 AN: 183361 AF XY: 0.000590

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000873 AC: 956 AN: 1095101 Hom.: 0 Cov.: 29 AF XY: 0.000834 AC XY: 301 AN XY: 361123

African (AFR) AF: 0.000342 AC: 9 AN: 26338

American (AMR) AF: 0.000341 AC: 12 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.0000740 AC: 4 AN: 54052

European-Finnish (FIN) AF: 0.000123 AC: 5 AN: 40532

Middle Eastern (MID) AF: 0.000311 AC: 1 AN: 3219

European-Non Finnish (NFE) AF: 0.00108 AC: 907 AN: 840244

Other (OTH) AF: 0.000392 AC: 18 AN: 45932

GnomAD4 genome AF: 0.000553 AC: 62 AN: 112067 Hom.: 0 Cov.: 23 AF XY: 0.000350 AC XY: 12 AN XY: 34245

African (AFR) AF: 0.0000972 AC: 3 AN: 30860

American (AMR) AF: 0.000566 AC: 6 AN: 10608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2696

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000940 AC: 50 AN: 53166

Other (OTH) AF: 0.00132 AC: 2 AN: 1514

Alfa AF: 0.000546 Hom.: 6

Bravo AF: 0.000525

EpiCase AF: 0.00180

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.1
DANN	Benign	0.52
PhyloP100		-0.088
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs199904356; hg19: chrX-73751364;