Genetic Variant SLC6A8:p.Pro382Pro (chrX-153693909-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_005629.4(SLC6A8):c.1146G>C(p.Pro382Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,045,856 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. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P382P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Consequence

SLC6A8
NM_005629.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.20

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22529107).

BP6

Variant X-153693909-G-C is Benign according to our data. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-153693909-G-C is described in CliVar as Likely_benign. Clinvar id is 2029055.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-5.2 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.1146G>C	p.Pro382Pro	synonymous_variant	Exon 8 of 13	ENST00000253122.10	NP_005620.1	P48029-1X5D9C4
SLC6A8	NM_001142805.2 link	c.1116G>C	p.Pro372Pro	synonymous_variant	Exon 8 of 13		NP_001136277.1	P48029Q59EV7
SLC6A8	NM_001142806.1 link	c.801G>C	p.Pro267Pro	synonymous_variant	Exon 8 of 13		NP_001136278.1	P48029-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10 link	c.1146G>C	p.Pro382Pro	synonymous_variant	Exon 8 of 13	1	NM_005629.4	ENSP00000253122.5		P48029-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000191

AC:

AN:

1045856

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

337640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24861

American (AMR)

AF:

0.00

AC:

AN:

28051

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18594

East Asian (EAS)

AF:

0.0000732

AC:

AN:

27314

South Asian (SAS)

AF:

0.00

AC:

AN:

49760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37095

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2862

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

813270

Other (OTH)

AF:

0.00

AC:

AN:

44049

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Creatine transporter deficiency

Benign:1

Sep 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.97

(source)

DANN

Benign

0.68

FATHMM_MKL

Benign

0.086

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.91

PhyloP100

-5.2

PROVEAN

Pathogenic

-8.0

REVEL

Benign

0.054

MutPred

0.24

Gain of methylation at G44 (P = 0.009);

MVP

0.49

ClinPred

0.83

GERP RS

-9.7

PromoterAI

0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over