Genetic Variant NM_005629.4:c.1184T>C (chrX-153693947-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_005629.4(SLC6A8):c.1184T>C(p.Leu395Pro) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L395L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.97

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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_005629.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

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.1184T>C	p.Leu395Pro	missense	Exon 8 of 13	NP_005620.1	P48029-1
SLC6A8	NM_001142805.2		c.1154T>C	p.Leu385Pro	missense	Exon 8 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.839T>C	p.Leu280Pro	missense	Exon 8 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.1184T>C	p.Leu395Pro	missense	Exon 8 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.1184T>C	p.Leu395Pro	missense	Exon 8 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.1184T>C	p.Leu395Pro	missense	Exon 8 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1060566

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

345554

African (AFR)

AF:

0.00

AC:

AN:

25514

American (AMR)

AF:

0.00

AC:

AN:

29231

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18757

East Asian (EAS)

AF:

0.00

AC:

AN:

28162

South Asian (SAS)

AF:

0.00

AC:

AN:

50521

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3011

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

823041

Other (OTH)

AF:

0.00

AC:

AN:

44643

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Creatine transporter deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.2

PhyloP100

5.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.76

Sift

Benign

0.038

Sift4G

Uncertain

0.010

Polyphen

0.99

Vest4

0.73

MutPred

0.57

Loss of stability (P = 0.0414)

MVP

0.92

MPC

3.1

ClinPred

0.99

GERP RS

4.8

PromoterAI

0.0077

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.96

Mutation Taster

=19/81

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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