X-153688666-C-T

Position:

chrX-153688666-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.92C>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a methionine at amino acid position 31 (p.Pro31Leu). This variant has been previously reported in one individual with seizures, neurological regression, and spasticity (PMID:31222513), who was found by exome sequencing to be hemizygous for the variant; however, biochemical studies were not reported for this individual, such that neither PP4 nor PS4 apply. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00013 (4/30763 alleles, 1 hemizygote), which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.114 (BP4). There is a ClinVar entry for this variant (Variation ID:572616). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA415076214/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.000065 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.000038 ( 0 hom. 13 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4B:2

Conservation

PhyloP100: 1.17

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 -1 ACMG points.

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 link	c.92C>T	p.Pro31Leu	missense_variant	1/13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.92C>T	p.Pro31Leu	missense_variant	1/13		NP_001136277.1	P48029Q59EV7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC6A8	ENST00000253122.10 link	c.92C>T	p.Pro31Leu	missense_variant	1/13	1	NM_005629.4	ENSP00000253122.5	P48029-1
PNCK	ENST00000458354.5 link	c.-3+149G>A		intron_variant		3		ENSP00000401542.1	C9J2B9
PNCK	ENST00000480693.1 link	n.64+149G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000832

AC:

AN:

108178

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

31496

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:

0.0218

Gnomad NFE

AF:

0.0000777

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000329

AC:

AN:

60779

Hom.:

AF XY:

0.00

AC XY:

AN XY:

19963

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000382

AC:

AN:

969021

Hom.:

Cov.:

AF XY:

0.0000422

AC XY:

AN XY:

307803

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:

0.0000468

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000322

Gnomad4 OTH exome

AF:

0.0000506

GnomAD4 genome

AF:

0.0000647

AC:

AN:

108195

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

31521

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:

0.0000777

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000466

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Nov 08, 2024	The NM_005629.4:c.92C>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a methionine at amino acid position 31 (p.Pro31Leu). This variant has been previously reported in one individual with seizures, neurological regression, and spasticity (PMID: 31222513), who was found by exome sequencing to be hemizygous for the variant; however, biochemical studies were not reported for this individual, such that neither PP4 nor PS4 apply. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00013 (4/30763 alleles, 1 hemizygote), which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.114 (BP4). There is a ClinVar entry for this variant (Variation ID:572616). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2021	This variant is associated with the following publications: (PMID: 31222513) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.77

REVEL

Benign

0.11

Sift

Benign

0.033

Sift4G

Uncertain

0.012

Polyphen

0.0040

Vest4

0.10

MutPred

0.23

Loss of loop (P = 0.1242);

MVP

0.17

MPC

1.2

ClinPred

0.10

GERP RS

2.8

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.16

gMVP

0.22

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