X-153688666-C-G

Variant names:

• chrX-153688666-C-G
• rs868950793
• NM_005629.4:c.92C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005629.4(SLC6A8):​c.92C>G​(p.Pro31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,077,205 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes 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: 𝑓 0.0000092 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000019 (0 hom. 11 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 3 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]

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23015213).
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.92C>G	p.Pro31Arg	missense_variant	Exon 1 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.92C>G	p.Pro31Arg	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.92C>G	p.Pro31Arg	missense_variant	Exon 1 of 13	1	NM_005629.4	ENSP00000253122.5
PNCK	ENST00000458354.5	c.-3+149G>C		intron_variant	Intron 1 of 3	3		ENSP00000401542.1
PNCK	ENST00000480693.1	n.64+149G>C		intron_variant	Intron 1 of 3	5
SLC6A8	ENST00000476466.1	n.-57C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000924 AC: 1 AN: 108180 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000194

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 1 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: 0.0000457

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 18 AN: 969025 Hom.: 0 Cov.: 26 AF XY: 0.0000357 AC XY: 11 AN XY: 307807

African (AFR) AF: 0.00 AC: 0 AN: 19852

American (AMR) AF: 0.00 AC: 0 AN: 18370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15723

East Asian (EAS) AF: 0.00 AC: 0 AN: 20001

South Asian (SAS) AF: 0.00 AC: 0 AN: 42703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34063

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2764

European-Non Finnish (NFE) AF: 0.0000219 AC: 17 AN: 775988

Other (OTH) AF: 0.0000253 AC: 1 AN: 39561

GnomAD4 genome AF: 0.00000924 AC: 1 AN: 108180 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31496

African (AFR) AF: 0.00 AC: 0 AN: 30209

American (AMR) AF: 0.00 AC: 0 AN: 10499

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2597

East Asian (EAS) AF: 0.00 AC: 0 AN: 3296

South Asian (SAS) AF: 0.00 AC: 0 AN: 2593

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 229

European-Non Finnish (NFE) AF: 0.0000194 AC: 1 AN: 51458

Other (OTH) AF: 0.00 AC: 0 AN: 1466

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.18
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.020	D
Vest4		0.15
ClinPred		0.15	T
GERP RS		2.8
PromoterAI		-0.011	Neutral
Varity_R		0.27
gMVP		0.16
Mutation Taster		=85/15	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

Other links and lift over

dbSNP: rs868950793; hg19: chrX-152954121;