Genetic Variant SLC6A8:p.Pro31Gln (chrX-153688666-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005629.4(SLC6A8):c.92C>A(p.Pro31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000103 in 969,025 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P31L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000010 ( 0 hom. 0 hem. )

Consequence

SLC6A8
NM_005629.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.17

Publications

3 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 links:

PNCK (HGNC:13415): (pregnancy up-regulated nonubiquitous CaM kinase) PNCK is a member of the calcium/calmodulin-dependent protein kinase family of protein serine/threonine kinases (see CAMK1; MIM 604998) (Gardner et al., 2000 [PubMed 10673339]).[supplied by OMIM, Mar 2008]

PNCK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24598551).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4 link	c.92C>A	p.Pro31Gln	missense_variant	Exon 1 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2 link	c.92C>A	p.Pro31Gln	missense_variant	Exon 1 of 13		NP_001136277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC6A8	ENST00000253122.10 link	c.92C>A	p.Pro31Gln	missense_variant	Exon 1 of 13	1	NM_005629.4	ENSP00000253122.5
PNCK	ENST00000458354.5 link	c.-3+149G>T		intron_variant	Intron 1 of 3	3		ENSP00000401542.1
PNCK	ENST00000480693.1 link	n.64+149G>T		intron_variant	Intron 1 of 3	5
SLC6A8	ENST00000476466.1 link	n.-57C>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

60779

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000103

AC:

AN:

969025

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

307807

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19852

American (AMR)

AF:

0.00

AC:

AN:

18370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15723

East Asian (EAS)

AF:

0.00

AC:

AN:

20001

South Asian (SAS)

AF:

0.00

AC:

AN:

42703

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34063

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2764

European-Non Finnish (NFE)

AF:

0.00000129

AC:

AN:

775988

Other (OTH)

AF:

0.00

AC:

AN:

39561

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Benign

0.083

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.48

REVEL

Benign

0.19

Sift

Uncertain

0.025

Sift4G

Uncertain

0.022

Vest4

0.15

ClinPred

0.24

GERP RS

2.8

PromoterAI

0.065

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.17

gMVP

0.18

Mutation Taster

=85/15

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