X-153688666-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.92C>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a proline by a methionine at amino acid position 31 (p.Pro31Leu). This variant has been previously reported in one individual with seizures, neurological regression, and spasticity (PMID:31222513), who was found by exome sequencing to be hemizygous for the variant; however, biochemical studies were not reported for this individual, such that neither PP4 nor PS4 apply. In gnomAD v2.1.1, the highest population minor allele frequency is 0.00013 (4/30763 alleles, 1 hemizygote), which is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. The computational predictor REVEL gives a score of 0.114 (BP4). There is a ClinVar entry for this variant (Variation ID:572616). 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 CCDS VCEP (Specifications Version 1.1.0): BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 8, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA415076214/MONDO:0010305/027

Frequency

Genomes: 𝑓 0.000065 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.000038 ( 0 hom. 13 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4B:2

Conservation

PhyloP100: 1.17

Publications

3 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: Uncertain_significance. The variant received -1 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.92C>T	p.Pro31Leu	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.92C>T	p.Pro31Leu	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.92C>T	p.Pro31Leu	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.92C>T	p.Pro31Leu	missense	Exon 1 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.92C>T	p.Pro31Leu	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

AF:

0.0000832

AC:

AN:

108178

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:

0.00

Gnomad MID

AF:

0.0218

Gnomad NFE

AF:

0.0000777

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000329

AC:

AN:

60779

AF XY:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.0000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000382

AC:

AN:

969021

Hom.:

Cov.:

AF XY:

0.0000422

AC XY:

AN XY:

307803

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19852

American (AMR)

AF:

0.00

AC:

AN:

18370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15723

East Asian (EAS)

AF:

0.00

AC:

AN:

20001

South Asian (SAS)

AF:

0.0000468

AC:

AN:

42701

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34063

Middle Eastern (MID)

AF:

0.00289

AC:

AN:

2764

European-Non Finnish (NFE)

AF:

0.0000322

AC:

AN:

775986

Other (OTH)

AF:

0.0000506

AC:

AN:

39561

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0000647

AC:

AN:

108195

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

31521

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30252

American (AMR)

AF:

0.00

AC:

AN:

10508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2595

East Asian (EAS)

AF:

0.00

AC:

AN:

3286

South Asian (SAS)

AF:

0.00

AC:

AN:

2580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5196

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.0000777

AC:

AN:

51450

Other (OTH)

AF:

0.00

AC:

AN:

1485

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000466

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine transporter deficiency (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.77

REVEL

Benign

0.11

Sift

Benign

0.033

Sift4G

Uncertain

0.012

Polyphen

0.0040

Vest4

0.10

MutPred

0.23

Loss of loop (P = 0.1242)

MVP

0.17

MPC

1.2

ClinPred

0.10

GERP RS

2.8

PromoterAI

-0.0015

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.16

gMVP

0.22

Mutation Taster

=86/14

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