NM_005629.4:c.12G>C

Variant names:

• chrX-153688586-G-C
• rs1486125548
• NM_005629.4:c.12G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005629.4(SLC6A8):​c.12G>C​(p.Lys4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000384 in 1,042,912 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. 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. K4R) has been classified as Uncertain significance. The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.0000021 (0 hom. 0 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0820
• 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

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13588709).

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.12G>C	p.Lys4Asn	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.12G>C	p.Lys4Asn	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.12G>C	p.Lys4Asn	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.12G>C	p.Lys4Asn	missense	Exon 1 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.12G>C	p.Lys4Asn	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.0000190 AC: 2 AN: 105114 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: 0.0000396

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 2 AN: 937798 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 296840

African (AFR) AF: 0.00 AC: 0 AN: 19193

American (AMR) AF: 0.00 AC: 0 AN: 17398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14845

East Asian (EAS) AF: 0.00 AC: 0 AN: 17938

South Asian (SAS) AF: 0.00 AC: 0 AN: 40686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2433

European-Non Finnish (NFE) AF: 0.00000264 AC: 2 AN: 756706

Other (OTH) AF: 0.00 AC: 0 AN: 37475

GnomAD4 genome AF: 0.0000190 AC: 2 AN: 105114 Hom.: 0 Cov.: 20 AF XY: 0.0000343 AC XY: 1 AN XY: 29182

African (AFR) AF: 0.00 AC: 0 AN: 29296

American (AMR) AF: 0.00 AC: 0 AN: 10239

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2566

East Asian (EAS) AF: 0.00 AC: 0 AN: 3201

South Asian (SAS) AF: 0.00 AC: 0 AN: 2460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4593

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 223

European-Non Finnish (NFE) AF: 0.0000396 AC: 2 AN: 50492

Other (OTH) AF: 0.00 AC: 0 AN: 1434

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Creatine transporter deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.082
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.10
Sift	Benign	0.23	T
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.22		Loss of ubiquitination at K4 (P = 0.0067)
MVP		0.34
MPC		1.4
ClinPred		0.11	T
GERP RS		2.6
PromoterAI		-0.0064	Neutral
Varity_R		0.18
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: rs1486125548; hg19: chrX-152954041;