X-153695194-G-C

Variant names:

• chrX-153695194-G-C
• rs373570632
• NM_005629.4:c.1888G>C
• SLC6A8 p.Val630Leu

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005629.4(SLC6A8):​c.1888G>C​(p.Val630Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000932 in 1,072,403 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V630M) has been classified as Uncertain significance. The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.68
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P, Orphanet

ACMG classification

Specifications for SLC6A8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047998518).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.1888G>C	p.Val630Leu	missense	Exon 13 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1858G>C	p.Val620Leu	missense	Exon 13 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1543G>C	p.Val515Leu	missense	Exon 13 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1888G>C	p.Val630Leu	missense	Exon 13 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1885G>C	p.Val629Leu	missense	Exon 13 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1879G>C	p.Val627Leu	missense	Exon 13 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.32e-7 AC: 1 AN: 1072403 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 348481

African (AFR) AF: 0.00 AC: 0 AN: 25726

American (AMR) AF: 0.00 AC: 0 AN: 32301

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18971

East Asian (EAS) AF: 0.00 AC: 0 AN: 28692

South Asian (SAS) AF: 0.00 AC: 0 AN: 51138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38295

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3814

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 828367

Other (OTH) AF: 0.00 AC: 0 AN: 45099

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Benign	0.45
DEOGEN2	Benign	0.096	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.20	N
PhyloP100		3.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.050	N
REVEL	Benign	0.094
Sift	Benign	0.77	T
Sift4G	Benign	0.65	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.59
Mutation Taster		=92/8	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373570632;

hg19: chrX-152960649;