chrX-153688600-G-T

Position:

chrX-153688600-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4: c.26G>T variant in SLC6A8 is a missense variant predicted to cause substitution of Glycine for Valine at amino acid 9 (p.Gly9Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00019 (14/74655 alleles) in the European population. Additionally, there are 5 hemizygotes in gnomAD v2.1.1, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (<5 hemizygotes in gnomAD). The computational predictor REVEL gives a score of 0.146 which is below the threshold of 0.25, evidence that does not predict a damaging effect on SLC6A8 function (PP3). 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:571505). In summary, this variant meets the criteria to be classified as Likely Benign 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): BS1, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA415075922/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.000057 ( 0 hom., 2 hem., cov: 20)

Exomes 𝑓: 0.000038 ( 0 hom. 14 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:3

Conservation

PhyloP100: 0.962

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 Likely_benign. Variant got -5 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4 linkuse as main transcript	c.26G>T	p.Gly9Val	missense_variant	1/13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 linkuse as main transcript	c.26G>T	p.Gly9Val	missense_variant	1/13		NP_001136277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 linkuse as main transcript	c.26G>T	p.Gly9Val	missense_variant	1/13	1	NM_005629.4	ENSP00000253122	P1	P48029-1
PNCK	ENST00000458354.5 linkuse as main transcript	c.-3+215C>A		intron_variant		3		ENSP00000401542
PNCK	ENST00000480693.1 linkuse as main transcript	n.64+215C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000569

AC:

AN:

105524

Hom.:

Cov.:

AF XY:

0.0000680

AC XY:

AN XY:

29418

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000844

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000395

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000205

AC:

AN:

58513

Hom.:

AF XY:

0.000196

AC XY:

AN XY:

20385

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00137

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

956786

Hom.:

Cov.:

AF XY:

0.0000458

AC XY:

AN XY:

305386

show subpopulations

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:

0.000826

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000569

AC:

AN:

105524

Hom.:

Cov.:

AF XY:

0.0000680

AC XY:

AN XY:

29418

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000844

Gnomad4 NFE

AF:

0.0000395

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2023	- -
Likely benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_005629.4: c.26G>T variant in SLC6A8 is a missense variant predicted to cause substitution of Glycine for Valine at amino acid 9 (p.Gly9Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00019 (14/74655 alleles) in the European population. Additionally, there are 5 hemizygotes in gnomAD v2.1.1, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (<5 hemizygotes in gnomAD). The computational predictor REVEL gives a score of 0.146 which is below the threshold of 0.25, evidence that does not predict a damaging effect on SLC6A8 function (PP3). 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:571505). In summary, this variant meets the criteria to be classified as Likely Benign 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): BS1, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Creatine deficiency syndrome 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.3

REVEL

Benign

0.15

Sift

Benign

0.20

Sift4G

Uncertain

0.018

Polyphen

0.91

Vest4

0.23

MutPred

0.33

Gain of sheet (P = 0.0028);

MVP

0.54

MPC

1.6

ClinPred

0.098

GERP RS

2.6

Varity_R

0.18

gMVP

0.37

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