rs149024147

Positions:

chrX-153691453-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BS1BS2

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.544G>A variant in SLC6A8 is a missense variant predicted to cause substitution of valine by methionine at amino acid 182 (p.Val182Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00084 (16/19086 alleles) in the African/African American population, meeting the CCDS VCEP’s allele frequency threshold for BS1 (>0.0002) (BS1). This variant is present in 5 or more hemizygotes in gnomAD v2.1.1 (BS2). Furthermore, the variant did not segregate with intellectual disability in multiple brothers, and the proband with the variant had normal urine creatine and normal cerebral creatine on 1H-magnetic resonance spectroscopy (PMID 16738945). The computational predictor REVEL gives a score of 0.184, evidence that does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact of the variant on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 465147). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549204/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., 13 hem., cov: 25)

Exomes 𝑓: 0.000031 ( 0 hom. 12 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: 1.43

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

BS1

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC6A8	NM_005629.4 linkuse as main transcript	c.544G>A	p.Val182Met	missense_variant	3/13	ENST00000253122.10
SLC6A8	NM_001142805.2 linkuse as main transcript	c.544G>A	p.Val182Met	missense_variant	3/13
SLC6A8	NM_001142806.1 linkuse as main transcript	c.199G>A	p.Val67Met	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.544G>A	p.Val182Met	missense_variant	3/13	1	NM_005629.4	P1	P48029-1

Frequencies

GnomAD3 genomes

AF:

0.000300

AC:

AN:

113232

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

AN XY:

35388

show subpopulations

Gnomad AFR

AF:

0.000928

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:

0.0000938

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000546

AC:

AN:

183125

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

67785

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1097592

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

363182

show subpopulations

Gnomad4 AFR exome

AF:

0.000758

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000950

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.000300

AC:

AN:

113232

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

AN XY:

35388

show subpopulations

Gnomad4 AFR

AF:

0.000928

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:

0.0000938

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000246

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2020	This variant is associated with the following publications: (PMID: 16738945) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Creatine transporter deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_005629.4:c.544G>A variant in SLC6A8 is a missense variant predicted to cause substitution of valine by methionine at amino acid 182 (p.Val182Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00084 (16/19086 alleles) in the African/African American population, meeting the CCDS VCEP’s allele frequency threshold for BS1 (>0.0002) (BS1). This variant is present in 5 or more hemizygotes in gnomAD v2.1.1 (BS2). Furthermore, the variant did not segregate with intellectual disability in multiple brothers, and the proband with the variant had normal urine creatine and normal cerebral creatine on 1H-magnetic resonance spectroscopy (PMID 16738945). The computational predictor REVEL gives a score of 0.184, evidence that does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact of the variant on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 465147). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

0.60

N;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.95

N;N

REVEL

Benign

0.18

Sift

Benign

0.19

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.13

B;.

Vest4

0.22

MVP

0.69

MPC

1.3

ClinPred

0.020

GERP RS

3.1

Varity_R

0.24

gMVP

0.64

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