X-153688585-A-G

Position:

chrX-153688585-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.11A>G variant in SLC6A8 is predicted to result in the missense substitution of lysine by arginine at amino acid 4 (p.Lys4Arg). The variant has been reported in a 15 year old hemizygous male with intellectual disability. Results of urine creatine level, creatine level on brain MRS, and creatine uptake studies are not available. There is insufficient evidence to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). When the variant was expressed in SLC6A8-deficient fibroblasts and creatine uptake was measured, the variant was reported to be non-pathogenic (Table 2). Compared to empty vector, expression of the variant increased creatine transport about 5 times, and expression of wild type SLC6A8 increased creatine transport about 6 times. However, because the assay was performed with 500uM creatine, and not <125uM (as required by the ClinGen CCDS VCEP), BS3 is not met. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.2, evidence that does not predict a damaging effect on SLC6A8 function (BP4). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes applied, as specified by the ClinGen CCDS VCEP: PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on January 11, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA415075865/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.0000097 ( 0 hom., 0 hem., cov: 20)

Exomes 𝑓: 0.0000011 ( 0 hom. 0 hem. )

Consequence

SLC6A8
ENST00000253122.10 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 0.457

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:

PNCK (HGNC:13415): (pregnancy up-regulated nonubiquitous CaM kinase) PNCK is a member of the calcium/calmodulin-dependent protein kinase family of protein serine/threonine kinases (see CAMK1; MIM 604998) (Gardner et al., 2000 [PubMed 10673339]).[supplied by OMIM, Mar 2008]

PNCK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4 linkuse as main transcript	c.11A>G	p.Lys4Arg	missense_variant	1/13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 linkuse as main transcript	c.11A>G	p.Lys4Arg	missense_variant	1/13		NP_001136277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.11A>G	p.Lys4Arg	missense_variant	1/13	1	NM_005629.4	ENSP00000253122	P1	P48029-1
PNCK	ENST00000458354.5 linkuse as main transcript	c.-3+230T>C		intron_variant		3		ENSP00000401542
PNCK	ENST00000480693.1 linkuse as main transcript	n.64+230T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000966

AC:

AN:

103516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28378

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:

0.0000200

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000107

AC:

AN:

931094

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

292626

show subpopulations

Gnomad4 AFR exome

AF:

0.0000526

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000966

AC:

AN:

103516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

28378

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:

0.0000200

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jan 11, 2024	The NM_005629.4:c.11A>G variant in SLC6A8 is predicted to result in the missense substitution of lysine by arginine at amino acid 4 (p.Lys4Arg). The variant has been reported in a 15 year old hemizygous male with intellectual disability. Results of urine creatine level, creatine level on brain MRS, and creatine uptake studies are not available. There is insufficient evidence to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). When the variant was expressed in SLC6A8-deficient fibroblasts and creatine uptake was measured, the variant was reported to be non-pathogenic (Table 2). Compared to empty vector, expression of the variant increased creatine transport about 5 times, and expression of wild type SLC6A8 increased creatine transport about 6 times. However, because the assay was performed with 500uM creatine, and not <125uM (as required by the ClinGen CCDS VCEP), BS3 is not met. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.2, evidence that does not predict a damaging effect on SLC6A8 function (BP4). In summary, the variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes applied, as specified by the ClinGen CCDS VCEP: PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on January 11, 2024) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2022	Experimental studies have shown that this missense change affects SLC6A8 function (PMID: 17465020). 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. 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 SLC6A8 protein function. This missense change has been observed in individual(s) with creatine transporter deficiency (PMID: 16738945). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 4 of the SLC6A8 protein (p.Lys4Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.26

REVEL

Benign

0.085

Sift

Benign

0.25

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.13

MutPred

0.23

Loss of ubiquitination at K4 (P = 0.0067);

MVP

0.15

MPC

1.0

ClinPred

0.055

GERP RS

2.6

Varity_R

0.14

gMVP

0.19

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