rs199635059

Positions:

• chrX-153694771-C-A
• chrX-153694771-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000253122.10(SLC6A8):​c.1649C>A​(p.Thr550Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,389 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. 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. T550S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: SLC6A8 ENST00000253122.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.340

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in ENST00000253122.10
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34018558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.1649C>A	p.Thr550Asn	missense_variant	12/13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.1619C>A	p.Thr540Asn	missense_variant	12/13		NP_001136277.1
SLC6A8	NM_001142806.1	c.1304C>A	p.Thr435Asn	missense_variant	12/13		NP_001136278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A8	ENST00000253122.10	c.1649C>A	p.Thr550Asn	missense_variant	12/13	1	NM_005629.4	ENSP00000253122	P1
SLC6A8	ENST00000430077.6	c.1304C>A	p.Thr435Asn	missense_variant	12/13	2		ENSP00000403041
SLC6A8	ENST00000485324.1	n.1956C>A		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096389 Hom.: 0 Cov.: 38 AF XY: 0.00000276 AC XY: 1 AN XY: 362153

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: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.91	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.14
Sift	Benign	0.15	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.037	B;.
Vest4		0.44
MutPred		0.33		Loss of glycosylation at T550 (P = 0.0814);.;
MVP		0.39
MPC		0.39
ClinPred		0.70	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-152960226;