NM_005629.4:c.1145C>T

Variant names:

• chrX-153693908-C-T
• rs1557045250
• NM_005629.4:c.1145C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4_Strong PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1145C>T variant in SLC6A8 is a missense variant predicted to cause substitution of Proline for Leucine at amino acid 382 (p.Pro382Leu). This variant is absent from gnomADv2.1.1, and has been reported in two individuals in the literature. In one affected individual in the literature, the ratio of urine Creatine to Creatinine was >99th percentile of normal, and reduced creatine uptake in patient fibroblasts was reported. In silico predictor REVEL suggests this variant will have a damaging / pathogenic effect on the protein (score=0.906). There is a ClinVar entry for this variant (Variation ID: 533700, 1 star review status) with 5 submitters classifying the variant with conflicting interpretations (Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)).In summary, this variant meets the criteria to be classified as Likely Pathogenic 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 1.0): PP4_Strong, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA415086073/MONDO:0010305/027

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: 7.78
• Publications: 1 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1145C>T	p.Pro382Leu	missense	Exon 8 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1115C>T	p.Pro372Leu	missense	Exon 8 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.800C>T	p.Pro267Leu	missense	Exon 8 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1145C>T	p.Pro382Leu	missense	Exon 8 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1145C>T	p.Pro382Leu	missense	Exon 8 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1145C>T	p.Pro382Leu	missense	Exon 8 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 114879 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1044291 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 336455

African (AFR) AF: 0.00 AC: 0 AN: 24793

American (AMR) AF: 0.00 AC: 0 AN: 28027

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18579

East Asian (EAS) AF: 0.00 AC: 0 AN: 27288

South Asian (SAS) AF: 0.00 AC: 0 AN: 49714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2857

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 811941

Other (OTH) AF: 0.00 AC: 0 AN: 43994

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Creatine transporter deficiency (6)
1	-	-	Intellectual disability (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.89		Loss of disorder (P = 0.038)
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1557045250; hg19: chrX-152959363;