rs1557043854

Variant names:

• chrX-153688764-T-C
• rs1557043854
• NM_005629.4:c.190T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005629.4(SLC6A8):​c.190T>C​(p.Ser64Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

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]

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.190T>C	p.Ser64Pro	missense_variant	Exon 1 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.190T>C	p.Ser64Pro	missense_variant	Exon 1 of 13		NP_001136277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.190T>C	p.Ser64Pro	missense_variant	Exon 1 of 13	1	NM_005629.4	ENSP00000253122.5
PNCK	ENST00000458354.5	c.-3+51A>G		intron_variant	Intron 1 of 3	3		ENSP00000401542.1
SLC6A8	ENST00000476466.1	n.42T>C		non_coding_transcript_exon_variant	Exon 1 of 3	3
PNCK	ENST00000480693.1	n.64+51A>G		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1028011 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 333889

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 28, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	4.1	H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.89		Loss of stability (P = 0.2897);
MVP		0.91
MPC		2.7
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1557043854; hg19: chrX-152954219;