Genetic Variant SLC6A8:p.Val274Leu (chrX-153693083-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005629.4(SLC6A8):c.820G>C(p.Val274Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,469 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts 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. V274M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88

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 Gene-Disease associations (from GenCC):

creatine transporter deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

SLC6A8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4189157).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	NM_005629.4	MANE Select	c.820G>C	p.Val274Leu	missense	Exon 5 of 13	NP_005620.1	P48029-1
SLC6A8	NM_001142805.2		c.820G>C	p.Val274Leu	missense	Exon 5 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.475G>C	p.Val159Leu	missense	Exon 5 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.820G>C	p.Val274Leu	missense	Exon 5 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.820G>C	p.Val274Leu	missense	Exon 5 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.820G>C	p.Val274Leu	missense	Exon 5 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096469

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362205

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26375

American (AMR)

AF:

0.00

AC:

AN:

35181

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19371

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.00

AC:

AN:

54052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3573

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841246

Other (OTH)

AF:

0.00

AC:

AN:

45994

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.42

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

2.0

PhyloP100

1.9

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.45

Sift

Benign

0.034

Sift4G

Uncertain

0.049

Polyphen

0.11

Vest4

0.24

MutPred

0.70

Loss of sheet (P = 0.0817)

MVP

0.82

MPC

1.2

ClinPred

0.83

GERP RS

4.9

PromoterAI

-0.0090

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Varity_R

0.29

gMVP

0.64

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over