X-153688622-C-A

Position:

• chrX-153688622-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BP4 PM2_Supporting

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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A8	NM_005629.4	c.48C>A	p.Asp16Glu	missense_variant	1/13	ENST00000253122.10
SLC6A8	NM_001142805.2	c.48C>A	p.Asp16Glu	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A8	ENST00000253122.10	c.48C>A	p.Asp16Glu	missense_variant	1/13	1	NM_005629.4	P1
PNCK	ENST00000458354.5	c.-3+193G>T		intron_variant		3
PNCK	ENST00000480693.1	n.64+193G>T		intron_variant, non_coding_transcript_variant		5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 16 of the SLC6A8 protein (p.Asp16Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC6A8-related conditions. ClinVar contains an entry for this variant (Variation ID: 392671). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC6A8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	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). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2017

A variant of uncertain significance has been identified in the SLC6A8 gene. The D16E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although the D16E variant is not observed in large population cohorts, the data is noted to have reduced depth of sequencing reads and therefore may be unreliable (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved in mammals. However, the D16E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.80	N
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
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.047
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs1057524586; hg19: chrX-152954077;