Genetic Variant SLC6A8:p.Val630Leu (chrX-153695194-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005629.4(SLC6A8):c.1888G>C(p.Val630Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000932 in 1,072,403 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V630M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.68

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, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

SLC6A8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047998518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.1888G>C	p.Val630Leu	missense_variant	Exon 13 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1858G>C	p.Val620Leu	missense_variant	Exon 13 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.1543G>C	p.Val515Leu	missense_variant	Exon 13 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A8	ENST00000253122.10 link	c.1888G>C	p.Val630Leu	missense_variant	Exon 13 of 13	1	NM_005629.4	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000430077.6 link	c.1543G>C	p.Val515Leu	missense_variant	Exon 13 of 13	2		ENSP00000403041.2	P48029-4
SLC6A8	ENST00000485324.1 link	n.2195G>C		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.32e-7

AC:

AN:

1072403

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

348481

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25726

American (AMR)

AF:

0.00

AC:

AN:

32301

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18971

East Asian (EAS)

AF:

0.00

AC:

AN:

28692

South Asian (SAS)

AF:

0.00

AC:

AN:

51138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38295

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3814

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

828367

Other (OTH)

AF:

0.00

AC:

AN:

45099

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.096

T;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.20

N;.

PhyloP100

3.7

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.050

N;N

REVEL

Benign

0.094

Sift

Benign

0.77

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.0020

B;.

Vest4

0.025

MutPred

0.21

Loss of catalytic residue at V630 (P = 0.0071);.;

MVP

0.068

MPC

0.15

ClinPred

0.39

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.59

Mutation Taster

=92/8

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over