Genetic Variant NM_005629.4:c.1678A>G (chrX-153694800-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M560I) has been classified as 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:7

Conservation

PhyloP100: 0.0700

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

creatine transporter deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

SLC6A8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_005629.4

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 Benign/Likely_benign. ClinVar VariationId is 378616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 27 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC6A8	NM_005629.4	MANE Select	c.1678A>G	p.Met560Val	missense	Exon 12 of 13	NP_005620.1
SLC6A8	NM_001142805.2		c.1648A>G	p.Met550Val	missense	Exon 12 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.1333A>G	p.Met445Val	missense	Exon 12 of 13	NP_001136278.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1678A>G	p.Met560Val	missense	Exon 12 of 13	ENSP00000253122.5
SLC6A8	ENST00000430077.6	TSL:2	c.1333A>G	p.Met445Val	missense	Exon 12 of 13	ENSP00000403041.2
SLC6A8	ENST00000485324.1	TSL:2	n.1985A>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes

AF:

0.000487

AC:

AN:

112858

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00160

AC:

291

AN:

181402

AF XY:

0.00277

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 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

African (AFR)

AF:

0.000531

AC:

AN:

26358

American (AMR)

AF:

0.000284

AC:

AN:

35185

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.0118

AC:

636

AN:

53989

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40215

Middle Eastern (MID)

AF:

0.00702

AC:

AN:

3560

European-Non Finnish (NFE)

AF:

0.000308

AC:

259

AN:

841317

Other (OTH)

AF:

0.00152

AC:

AN:

45984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000496

AC:

AN:

112909

Hom.:

Cov.:

AF XY:

0.000769

AC XY:

AN XY:

35103

show subpopulations

African (AFR)

AF:

0.0000642

AC:

AN:

31167

American (AMR)

AF:

0.0000925

AC:

AN:

10810

Ashkenazi Jewish (ASJ)

AF:

0.000754

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.00936

AC:

AN:

2777

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6262

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000319

AC:

AN:

53243

Other (OTH)

AF:

0.00326

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000463

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 15, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Creatine transporter deficiency

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

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

Jan 27, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Congenital cerebellar hypoplasia

Benign:1

Aug 21, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

7.4

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.083

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0097

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

PhyloP100

0.070

PrimateAI

Benign

0.28

PROVEAN

Benign

0.88

REVEL

Uncertain

0.37

Sift

Benign

0.49

Sift4G

Benign

0.45

Polyphen

0.0

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

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over