dbSNP rs797045972: SLC6A8:p.Thr325Arg (chrX-153693324-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_005629.4(SLC6A8):c.974C>G(p.Thr325Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T325T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.93

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_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant X-153693324-C-G is Pathogenic according to our data. Variant chrX-153693324-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 212216.Status of the report is criteria_provided_single_submitter, 1 stars.

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
SLC6A8	NM_005629.4	MANE Select	c.974C>G	p.Thr325Arg	missense	Exon 6 of 13	NP_005620.1
SLC6A8	NM_001142805.2		c.974C>G	p.Thr325Arg	missense	Exon 6 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.629C>G	p.Thr210Arg	missense	Exon 6 of 13	NP_001136278.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.974C>G	p.Thr325Arg	missense	Exon 6 of 13	ENSP00000253122.5
SLC6A8	ENST00000430077.6	TSL:2	c.629C>G	p.Thr210Arg	missense	Exon 6 of 13	ENSP00000403041.2
SLC6A8	ENST00000442457.1	TSL:3	c.56C>G	p.Thr19Arg	missense	Exon 1 of 5	ENSP00000403682.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Pathogenic:1

Nov 27, 2019

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.62

MutationAssessor

Pathogenic

3.3

PhyloP100

4.9

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.84

MutPred

0.81

Gain of methylation at T325 (P = 0.0042)

MVP

0.92

MPC

2.5

ClinPred

1.0

GERP RS

5.2

PromoterAI

-0.014

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.98

gMVP

0.98

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over