X-153688644-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_SupportingBP4

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

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 0.554

Variant links:

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 links:

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]

PNCK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 13		NP_001136277.1	P48029Q59EV7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A8	ENST00000253122.10 link	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 13	1	NM_005629.4	ENSP00000253122.5	P48029-1
PNCK	ENST00000458354.5 link	c.-3+171C>G		intron_variant	Intron 1 of 3	3		ENSP00000401542.1	C9J2B9
PNCK	ENST00000480693.1 link	n.64+171C>G		intron_variant	Intron 1 of 3	5
SLC6A8	ENST00000476466.1 link	n.-79G>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000930

AC:

AN:

107560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31010

show subpopulations

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

62731

Hom.:

AF XY:

0.00

AC XY:

AN XY:

21735

show subpopulations

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 SAS 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:

AN:

970401

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

309501

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000510

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

AF:

0.00000930

AC:

AN:

107565

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31027

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000956

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.10

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.39

REVEL

Benign

0.085

Sift

Benign

0.31

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.11

MutPred

0.27

Gain of catalytic residue at A24 (P = 0.0186);

MVP

0.10

MPC

1.5

ClinPred

0.028

GERP RS

2.6

Varity_R

0.082

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over