rs1198790754

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -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.

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.26G>T	p.Gly9Val	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.26G>T	p.Gly9Val	missense	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.26G>T	p.Gly9Val	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.26G>T	p.Gly9Val	missense	Exon 1 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.26G>T	p.Gly9Val	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

AF:

0.0000569

AC:

AN:

105524

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000205

AC:

AN:

58513

AF XY:

0.000196

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 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

African (AFR)

AF:

0.00

AC:

AN:

19644

American (AMR)

AF:

0.00

AC:

AN:

18729

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15377

East Asian (EAS)

AF:

0.00

AC:

AN:

18720

South Asian (SAS)

AF:

0.00

AC:

AN:

42553

European-Finnish (FIN)

AF:

0.000826

AC:

AN:

32684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2520

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

768002

Other (OTH)

AF:

0.00

AC:

AN:

38557

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000569

AC:

AN:

105524

Hom.:

Cov.:

AF XY:

0.0000680

AC XY:

AN XY:

29418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29362

American (AMR)

AF:

0.00

AC:

AN:

10287

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2557

East Asian (EAS)

AF:

0.00

AC:

AN:

3208

South Asian (SAS)

AF:

0.00

AC:

AN:

2449

European-Finnish (FIN)

AF:

0.000844

AC:

AN:

4741

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000395

AC:

AN:

50639

Other (OTH)

AF:

0.00

AC:

AN:

1441

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine transporter deficiency (2)

Creatine deficiency syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

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

PhyloP100

0.96

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

PromoterAI

0.13

Neutral

(source)

Varity_R

0.18

gMVP

0.37

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over