Genetic Variant SLC6A8:p.Gly39Asp (chrX-153688690-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4(SLC6A8):c.116G>A (p.Gly39Asp) variant in SLC6A8 is a missense variant predicted to cause substitution of Glycine for Aspartic Acid at amino acid 39 (p.Gly39Asp). This variant is absent from gnomAD v2.1.1, therefore PM2_Supporting criteria is applicable. The computational predictor REVEL gives a score of 0.107 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function, and SpliceAI predicts no impact on splicing (BP4). This variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:410221). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616458/MONDO:0010305/027

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 0.896

Publications

0 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 links:

PNCK (HGNC:13415): (pregnancy up-regulated nonubiquitous CaM kinase) PNCK is a member of the calcium/calmodulin-dependent protein kinase family of protein serine/threonine kinases (see CAMK1; MIM 604998) (Gardner et al., 2000 [PubMed 10673339]).[supplied by OMIM, Mar 2008]

PNCK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.116G>A	p.Gly39Asp	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.116G>A	p.Gly39Asp	missense	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.116G>A	p.Gly39Asp	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.116G>A	p.Gly39Asp	missense	Exon 1 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.116G>A	p.Gly39Asp	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1003854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

322112

African (AFR)

AF:

0.00

AC:

AN:

21259

American (AMR)

AF:

0.00

AC:

AN:

24867

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16421

East Asian (EAS)

AF:

0.00

AC:

AN:

21968

South Asian (SAS)

AF:

0.00

AC:

AN:

45821

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3075

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

793363

Other (OTH)

AF:

0.00

AC:

AN:

40956

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine transporter deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.093

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

0.90

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.76

REVEL

Benign

0.11

Sift

Benign

0.63

Sift4G

Benign

0.67

Polyphen

0.98

Vest4

0.17

MutPred

0.26

Loss of sheet (P = 0.0457)

MVP

0.43

MPC

1.6

ClinPred

0.10

GERP RS

2.3

PromoterAI

-0.064

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.12

gMVP

0.50

Mutation Taster

=88/12

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over