rs122453115

Variant names:

• chrX-153688833-G-A
• rs122453115
• NM_005629.4:c.259G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.259G>A variant in SLC6A8 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 87 (p.Gly87Arg). This variant is absent in population databases (PM2_Supporting) and has been described in the literature in an individual for whom biochemical testing could not be performed (PMID:15154114). The computational predictor REVEL gives a score of 0.961 which is above the thresholds predicting a damaging (>0.75) impact on SLC6A8 function (PP3). When fibroblasts deficient for this SLC6A8 variant were grown in the presence of a physiological Cr concentration (25uM), the average creatine uptake was just above the detection limit, whereas in the control fibroblasts it was significantly higher (PMID:17465020) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID:11700). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP, July 13, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256012/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
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 9.18
• Publications: 6 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]

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]

ACMG classification

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.259G>A	p.Gly87Arg	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.259G>A	p.Gly87Arg	missense	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.259G>A	p.Gly87Arg	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
	PNCK	ENST00000922477.1		c.-336C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000592536.1
	PNCK	ENST00000955616.1		c.-448C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000625675.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 998799 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 315857

African (AFR) AF: 0.00 AC: 0 AN: 21470

American (AMR) AF: 0.00 AC: 0 AN: 27018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16251

East Asian (EAS) AF: 0.00 AC: 0 AN: 22667

South Asian (SAS) AF: 0.00 AC: 0 AN: 44106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37087

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2933

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 786835

Other (OTH) AF: 0.00 AC: 0 AN: 40432

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Creatine transporter deficiency (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.95		Gain of methylation at G87 (P = 0.0254)
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		2.7
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		1.0
Mutation Taster		=40/60	disease causing (ClinVar)

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: rs122453115; hg19: chrX-152954288;