X-153688661-G-C

Variant names:

• chrX-153688661-G-C
• rs782373793
• NM_005629.4:c.87G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_005629.4(SLC6A8):c.87G>C (p.Gly29=) variant in SLC6A8 is a synonymous single nucleotide variant that does not change the amino acid sequence at this position. In gnomAD v2.1.1, the highest population minor allele frequency is 0.005489 (62/11296 alleles) in the European population, with 10 hemizygotes present. The presence of 10 hemizygotes in the gnomAD dataset meets BA1 standalone criteria for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (<10 hemizygotes in population database). This variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID:380589). In summary, this variant meets the criteria to be classified as Benign for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16608764/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.000083 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.000081 (2 hom. 15 hem.)
• Consequence: SLC6A8 ENST00000253122.10 synonymous
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.906
• 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: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000253122.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	NM_005629.4	MANE Select	c.87G>C	p.Gly29Gly	synonymous	Exon 1 of 13	NP_005620.1
	SLC6A8	NM_001142805.2		c.87G>C	p.Gly29Gly	synonymous	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.87G>C	p.Gly29Gly	synonymous	Exon 1 of 13	ENSP00000253122.5
	PNCK	ENST00000458354.5	TSL:3	c.-3+154C>G		intron	N/A	ENSP00000401542.1
	PNCK	ENST00000480693.1	TSL:5	n.64+154C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000834 AC: 9 AN: 107973 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000856

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000982 AC: 60 AN: 61074 AF XY: 0.000487

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000812 AC: 79 AN: 972822 Hom.: 2 Cov.: 26 AF XY: 0.0000482 AC XY: 15 AN XY: 310988

African (AFR) AF: 0.00 AC: 0 AN: 20012

American (AMR) AF: 0.00414 AC: 79 AN: 19080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15870

East Asian (EAS) AF: 0.00 AC: 0 AN: 19999

South Asian (SAS) AF: 0.00 AC: 0 AN: 43261

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 778011

Other (OTH) AF: 0.00 AC: 0 AN: 39701

GnomAD4 genome AF: 0.0000834 AC: 9 AN: 107973 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 31371

African (AFR) AF: 0.00 AC: 0 AN: 30159

American (AMR) AF: 0.000856 AC: 9 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2589

East Asian (EAS) AF: 0.00 AC: 0 AN: 3291

South Asian (SAS) AF: 0.00 AC: 0 AN: 2575

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5179

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51346

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000257

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Creatine transporter deficiency (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		-0.91
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	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: rs782373793; hg19: chrX-152954116;