rs797045971

Positions:

chrX-153694723-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_005629.4(SLC6A8):c.1601T>C(p.Ile534Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 112,224 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.0000082 ( 0 hom. 7 hem. )

Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

SLC6A8 (HGNC:11055): (solute carrier family 6 member 8) The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

SLC6A8 links:

SLC6A8 (HGNC:):

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant X-153694723-T-C is Benign according to our data. Variant chrX-153694723-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212211.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4 linkuse as main transcript	c.1601T>C	p.Ile534Thr	missense_variant	12/13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 linkuse as main transcript	c.1571T>C	p.Ile524Thr	missense_variant	12/13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 linkuse as main transcript	c.1256T>C	p.Ile419Thr	missense_variant	12/13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.1601T>C	p.Ile534Thr	missense_variant	12/13	1	NM_005629.4	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000430077.6 linkuse as main transcript	c.1256T>C	p.Ile419Thr	missense_variant	12/13	2		ENSP00000403041.2	P48029-4
SLC6A8	ENST00000485324.1 linkuse as main transcript	n.1908T>C		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34414

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000820

AC:

AN:

1096970

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

362872

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000950

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34414

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000565

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2021	This sequence change replaces isoleucine with threonine at codon 534 of the SLC6A8 protein (p.Ile534Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SLC6A8-related conditions. ClinVar contains an entry for this variant (Variation ID: 212211). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 13, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 08, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Benign

0.17

DEOGEN2

Benign

0.19

T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.47

Sift

Benign

0.78

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.37

B;.

Vest4

0.80

MutPred

0.57

Loss of stability (P = 0.0185);.;

MVP

0.96

MPC

0.53

ClinPred

0.47

GERP RS

4.8

Varity_R

0.45

gMVP

0.91

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