dbSNP rs80338740: SLC6A8:p.Phe408del (chrX-153693978-GTTC-G) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3PM1PM2PM4_SupportingPP5_Very_Strong

The NM_005629.4(SLC6A8):c.1222_1224delTTC(p.Phe408del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 112,006 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000640028: Experimental studies have shown that this variant affects SLC6A8 function (PMID:22644605)." and additional evidence is available in ClinVar. The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:8O:3

Conservation

PhyloP100: 7.91

Publications

13 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

SLC6A8 links:

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ACMG classification

Specifications for SLC6A8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000640028: Experimental studies have shown that this variant affects SLC6A8 function (PMID: 22644605).; SCV004042597: "The variant was introduced into SLC6A8 cDNA by site-directed mutagenesis and expressed in Xenopus oocytes. Creatine transport was measured in the presence of 20uM creatine and was "severely impaired"" (PMID: 22644605).; SCV004121961: "The variant causes a loss of electrogenic and creatine transport activities in X. laevis oocytes (Valayannopoulos_2013)." PMID:23644449; SCV004847345: In vitro functional studies support that this variant results in decreased creatine uptake (Poo-Arguelles 2006 PMID: 16601898, Fons 2009 PMID: 19706062).; SCV000568382: Published functional studies indicate the variant impairs creatine uptake and did not generate any current in the presence of creatine, indicating that the electrogenic property and/or transport property was lost (Valayannopoulos et al., 2013);

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_005629.4

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_005629.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant X-153693978-GTTC-G is Pathogenic according to our data. Variant chrX-153693978-GTTC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11698.Status of the report is reviewed_by_expert_panel, 3 stars.

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	UniProt
SLC6A8	NM_005629.4	MANE Select	c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 8 of 13	NP_005620.1	P48029-1
SLC6A8	NM_001142805.2		c.1192_1194delTTC	p.Phe398del	conservative_inframe_deletion	Exon 8 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.877_879delTTC	p.Phe293del	conservative_inframe_deletion	Exon 8 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 8 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 8 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 8 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

112006

Hom.:

Cov.:

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:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1066528

Hom.:

AF XY:

0.00

AC XY:

AN XY:

346804

African (AFR)

AF:

0.00

AC:

AN:

25754

American (AMR)

AF:

0.00

AC:

AN:

30390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18841

East Asian (EAS)

AF:

0.00

AC:

AN:

28687

South Asian (SAS)

AF:

0.00

AC:

AN:

51017

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38079

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

825764

Other (OTH)

AF:

0.00

AC:

AN:

44861

GnomAD4 genome

AF:

0.00000893

AC:

AN:

112006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30823

American (AMR)

AF:

0.00

AC:

AN:

10656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6119

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53102

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000660

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine transporter deficiency (9)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.9

Mutation Taster

=28/72

disease causing (ClinVar)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over