rs1057524586

Variant names:

• chrX-153688622-C-A
• rs1057524586
• NM_005629.4:c.48C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-153688622-C-A
• chrX-153688622-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.48C>A variant in SLC6A8 is a missense variant predicted to result in substitution of aspartate by glutamate at amino acid 16 (p.Asp16Glu). The variant is absent in gnomAD v2.1.1, although low coverage is noted (PM2_Supporting). The computational predictor REVEL gives a score of 0.123, evidence that does not predict a damaging effect on SLC6A8 function (BP4). To our knowledge, this variant has not been reported in any patients with creatine transporter deficiency in the literature. There is a ClinVar entry for this variant (Variation ID: 392671). 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 LSD VCEP (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/CA16609138/MONDO:0010305/027

• Frequency:
  • Genomes: not found (cov: 20)
  • 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 U:3
• Conservation: PhyloP100: -0.956
• Publications: 0 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

Our verdict: Uncertain_significance. The variant received 0 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.48C>A	p.Asp16Glu	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.48C>A	p.Asp16Glu	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.48C>A	p.Asp16Glu	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.48C>A	p.Asp16Glu	missense	Exon 1 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.48C>A	p.Asp16Glu	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 968368 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 309460

African (AFR) AF: 0.00 AC: 0 AN: 19943

American (AMR) AF: 0.00 AC: 0 AN: 19669

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15784

East Asian (EAS) AF: 0.00 AC: 0 AN: 19384

South Asian (SAS) AF: 0.00 AC: 0 AN: 43688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 774154

Other (OTH) AF: 0.00 AC: 0 AN: 39394

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.9
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.96
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.12
Sift	Benign	0.78	T
Sift4G	Benign	0.37	T
Polyphen		0.95	P
Vest4		0.15
MutPred		0.17		Loss of loop (P = 0.0986)
MVP		0.40
MPC		1.1
ClinPred		0.043	T
GERP RS		1.7
PromoterAI		-0.0059	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.047
gMVP		0.11
Mutation Taster		=96/4	polymorphism

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: rs1057524586; hg19: chrX-152954077;