dbSNP rs1557043775: SLC6A8:p.Ala24Thr (chrX-153688644-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_005629.4(SLC6A8):c.70G>A(p.Ala24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A24P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000093 ( 0 hom., 1 hem., cov: 20)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.554

Publications

0 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 0 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_005629.4

BP4

Computational evidence support a benign effect (MetaRNN=0.10625857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.70G>A	p.Ala24Thr	missense_variant	Exon 1 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 link	c.70G>A	p.Ala24Thr	missense_variant	Exon 1 of 13		NP_001136277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC6A8	ENST00000253122.10 link	c.70G>A	p.Ala24Thr	missense_variant	Exon 1 of 13	1	NM_005629.4	ENSP00000253122.5
PNCK	ENST00000458354.5 link	c.-3+171C>T		intron_variant	Intron 1 of 3	3		ENSP00000401542.1
PNCK	ENST00000480693.1 link	n.64+171C>T		intron_variant	Intron 1 of 3	5
SLC6A8	ENST00000476466.1 link	n.-79G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000930

AC:

AN:

107560

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000333

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

970399

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

309499

African (AFR)

AF:

0.00

AC:

AN:

19982

American (AMR)

AF:

0.00

AC:

AN:

19625

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15898

East Asian (EAS)

AF:

0.00

AC:

AN:

19760

South Asian (SAS)

AF:

0.00

AC:

AN:

43627

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34079

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2684

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

775188

Other (OTH)

AF:

0.00

AC:

AN:

39556

GnomAD4 genome

AF:

0.00000930

AC:

AN:

107560

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

31010

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

29997

American (AMR)

AF:

0.00

AC:

AN:

10449

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2594

East Asian (EAS)

AF:

0.00

AC:

AN:

3303

South Asian (SAS)

AF:

0.00

AC:

AN:

2552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51286

Other (OTH)

AF:

0.00

AC:

AN:

1472

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.55

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.70

REVEL

Benign

0.077

Sift

Benign

0.55

Sift4G

Benign

0.74

Polyphen

0.029

Vest4

0.036

MutPred

0.20

Gain of glycosylation at A24 (P = 5e-04);

MVP

0.13

MPC

1.2

ClinPred

0.096

GERP RS

2.6

PromoterAI

-0.0058

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.042

gMVP

0.10

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over