chrX-153694800-A-G

Variant names:

• chrX-153694800-A-G
• rs145438966
• NM_005629.4:c.1678A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0700
• Publications: 7 publications found

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)

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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: 55 AN: 112858 Hom.: 1 Cov.: 25

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

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.: 5 Cov.: 37 AF XY: 0.00141 AC XY: 510 AN XY: 362125

African (AFR) AF: 0.000531 AC: 14 AN: 26358

American (AMR) AF: 0.000284 AC: 10 AN: 35185

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.0118 AC: 636 AN: 53989

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40215

Middle Eastern (MID) AF: 0.00702 AC: 25 AN: 3560

European-Non Finnish (NFE) AF: 0.000308 AC: 259 AN: 841317

Other (OTH) AF: 0.00152 AC: 70 AN: 45984

GnomAD4 genome AF: 0.000496 AC: 56 AN: 112909 Hom.: 1 Cov.: 25 AF XY: 0.000769 AC XY: 27 AN XY: 35103

African (AFR) AF: 0.0000642 AC: 2 AN: 31167

American (AMR) AF: 0.0000925 AC: 1 AN: 10810

Ashkenazi Jewish (ASJ) AF: 0.000754 AC: 2 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00936 AC: 26 AN: 2777

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6262

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.000319 AC: 17 AN: 53243

Other (OTH) AF: 0.00326 AC: 5 AN: 1536

Alfa AF: 0.000463 Hom.: 5

Bravo AF: 0.000321

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

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

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	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.4
DANN	Benign	0.67
DEOGEN2	Benign	0.083	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.070
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.88	N
REVEL	Uncertain	0.37
Sift	Benign	0.49	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.055
MVP		0.95
MPC		0.15
ClinPred		0.0094	T
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)

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

Other links and lift over

dbSNP: rs145438966; hg19: chrX-152960255; COSMIC: COSV107267981; COSMIC: COSV107267981;