chrX-153694800-A-G

Position:

chrX-153694800-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005629.4(SLC6A8):c.1678A>G(p.Met560Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000886 in 1,209,092 control chromosomes in the GnomAD database, including 6 homozygotes. There are 537 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00050 ( 1 hom., 27 hem., cov: 25)

Exomes 𝑓: 0.00093 ( 5 hom. 510 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0700

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009688646).

BP6

Variant X-153694800-A-G is Benign according to our data. Variant chrX-153694800-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 378616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153694800-A-G is described in Lovd as [Likely_benign]. Variant chrX-153694800-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000496 (56/112909) while in subpopulation SAS AF= 0.00936 (26/2777). AF 95% confidence interval is 0.00656. There are 1 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 27 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.1678A>G	p.Met560Val	missense_variant	12/13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1648A>G	p.Met550Val	missense_variant	12/13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.1333A>G	p.Met445Val	missense_variant	12/13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC6A8	ENST00000253122.10 link	c.1678A>G	p.Met560Val	missense_variant	12/13	1	NM_005629.4	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000430077.6 link	c.1333A>G	p.Met445Val	missense_variant	12/13	2		ENSP00000403041.2	P48029-4
SLC6A8	ENST00000485324.1 link	n.1985A>G		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes

AF:

0.000487

AC:

AN:

112858

Hom.:

Cov.:

AF XY:

0.000742

AC XY:

AN XY:

35042

show subpopulations

Gnomad AFR

AF:

0.0000643

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000926

Gnomad ASJ

AF:

0.000754

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00897

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.000319

Gnomad OTH

AF:

0.00330

GnomAD3 exomes

AF:

0.00160

AC:

291

AN:

181402

Hom.:

AF XY:

0.00277

AC XY:

185

AN XY:

66818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000256

Gnomad ASJ exome

AF:

0.000135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0125

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.00223

GnomAD4 exome

AF:

0.000926

AC:

1015

AN:

1096183

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

510

AN XY:

362125

show subpopulations

Gnomad4 AFR exome

AF:

0.000531

Gnomad4 AMR exome

AF:

0.000284

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.00152

GnomAD4 genome

AF:

0.000496

AC:

AN:

112909

Hom.:

Cov.:

AF XY:

0.000769

AC XY:

AN XY:

35103

show subpopulations

Gnomad4 AFR

AF:

0.0000642

Gnomad4 AMR

AF:

0.0000925

Gnomad4 ASJ

AF:

0.000754

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00936

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000319

Gnomad4 OTH

AF:

0.00326

Alfa

AF:

0.000669

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.00199

AC:

241

EpiCase

AF:

0.000763

EpiControl

AF:

0.000951

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -

Creatine transporter deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The p.Met560Val variant in SLC6A8 has been identified in at least 1 individual with creatine deficiency (PMID: 20717164), but has also been identified in >1% of South Asian chromosomes, 88 hemizygotes, and 1 homozygote by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for X-linked recessive creatine deficiency. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

7.4

DANN

Benign

0.67

DEOGEN2

Benign

0.083

T;.

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

N;.

PrimateAI

Benign

0.28

PROVEAN

Benign

0.88

N;N

REVEL

Uncertain

0.37

Sift

Benign

0.49

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.0

B;.

Vest4

0.055

MVP

0.95

MPC

0.15

ClinPred

0.0094

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.087

gMVP

0.60

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