rs2091435790

Variant names:

• chrX-153688581-A-G
• rs2091435790
• NM_005629.4:c.7A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005629.4(SLC6A8):​c.7A>G​(p.Lys3Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,024,037 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000098 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.0000043 (0 hom. 1 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0310
• 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]

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14864197).

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.7A>G	p.Lys3Glu	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.7A>G	p.Lys3Glu	missense	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.7A>G	p.Lys3Glu	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.7A>G	p.Lys3Glu	missense	Exon 1 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.7A>G	p.Lys3Glu	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.00000980 AC: 1 AN: 102053 Hom.: 0 Cov.: 20

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: 0.0000201

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000434 AC: 4 AN: 921984 Hom.: 0 Cov.: 22 AF XY: 0.00000347 AC XY: 1 AN XY: 288062

African (AFR) AF: 0.00 AC: 0 AN: 18756

American (AMR) AF: 0.00 AC: 0 AN: 16737

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14404

East Asian (EAS) AF: 0.00 AC: 0 AN: 17146

South Asian (SAS) AF: 0.00 AC: 0 AN: 39781

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29843

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2357

European-Non Finnish (NFE) AF: 0.00000536 AC: 4 AN: 746475

Other (OTH) AF: 0.00 AC: 0 AN: 36485

GnomAD4 genome AF: 0.00000980 AC: 1 AN: 102053 Hom.: 0 Cov.: 20 AF XY: 0.0000363 AC XY: 1 AN XY: 27581

African (AFR) AF: 0.00 AC: 0 AN: 28142

American (AMR) AF: 0.00 AC: 0 AN: 9962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2520

East Asian (EAS) AF: 0.00 AC: 0 AN: 3042

South Asian (SAS) AF: 0.00 AC: 0 AN: 2302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.0000201 AC: 1 AN: 49669

Other (OTH) AF: 0.00 AC: 0 AN: 1379

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Creatine transporter deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.031
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.14	N
REVEL	Benign	0.11
Sift	Benign	0.32	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.21		Loss of MoRF binding (P = 6e-04)
MVP		0.31
MPC		1.6
ClinPred		0.35	T
GERP RS		1.4
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0
Varity_R		0.22
gMVP		0.30
Mutation Taster		=95/5	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: rs2091435790; hg19: chrX-152954036;