X-153688644-G-C

Variant names:

• chrX-153688644-G-C
• rs1557043775
• NM_005629.4:c.70G>C

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(SLC6A8):c.70G>C (p.Ala24Pro) variant in SLC6A8 is a missense variant predicted to cause substitution of Alanine for Proline at amino acid 24 (p.Ala24Pro). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0000159 (1/62731 alleles) in the European population, with no hemi- or homozygotes, which is <0.0002 therefore PM2_Supporting criteria applicable. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function (BP4). To our knowledge, this variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID: 465148). 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/CA415076119/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 0.554
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.70G>C	p.Ala24Pro	missense	Exon 1 of 13	NP_005620.1
	SLC6A8	NM_001142805.2		c.70G>C	p.Ala24Pro	missense	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.70G>C	p.Ala24Pro	missense	Exon 1 of 13	ENSP00000253122.5
	PNCK	ENST00000458354.5	TSL:3	c.-3+171C>G		intron	N/A	ENSP00000401542.1
	PNCK	ENST00000480693.1	TSL:5	n.64+171C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000930 AC: 1 AN: 107560 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000957

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 1 AN: 62731 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000861

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 AF: 0.00000103 AC: 1 AN: 970401 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 309501

African (AFR) AF: 0.00 AC: 0 AN: 19982

American (AMR) AF: 0.0000510 AC: 1 AN: 19625

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15898

East Asian (EAS) AF: 0.00 AC: 0 AN: 19761

South Asian (SAS) AF: 0.00 AC: 0 AN: 43627

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 775188

Other (OTH) AF: 0.00 AC: 0 AN: 39557

GnomAD4 genome AF: 0.00000930 AC: 1 AN: 107565 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 31027

African (AFR) AF: 0.00 AC: 0 AN: 30037

American (AMR) AF: 0.0000956 AC: 1 AN: 10457

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2594

East Asian (EAS) AF: 0.00 AC: 0 AN: 3290

South Asian (SAS) AF: 0.00 AC: 0 AN: 2536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51277

Other (OTH) AF: 0.00 AC: 0 AN: 1488

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Creatine transporter deficiency Uncertain:2

Jun 06, 2022

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_005629.4(SLC6A8):c.70G>C (p.Ala24Pro) variant in SLC6A8 is a missense variant predicted to cause substitution of Alanine for Proline at amino acid 24 (p.Ala24Pro). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0000159 (1/62731 alleles) in the European population, with no hemi- or homozygotes, which is <0.0002 therefore PM2_Supporting criteria applicable. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function (BP4). To our knowledge, this variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID: 465148). 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).

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 24 of the SLC6A8 protein (p.Ala24Pro). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 465148). 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 with a negative predictive value of 95%. 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.

Creatine deficiency syndrome 1 Uncertain:1

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

SLC6A8-related disorder Uncertain:1

Jul 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC6A8 c.70G>C variant is predicted to result in the amino acid substitution p.Ala24Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0086% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.55
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.085
Sift	Benign	0.31	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.27		Gain of catalytic residue at A24 (P = 0.0186)
MVP		0.10
MPC		1.5
ClinPred		0.028	T
GERP RS		2.6
PromoterAI		-0.00060	Neutral
Varity_R		0.082
gMVP		0.32
Mutation Taster		=97/3	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: rs1557043775; hg19: chrX-152954099;