NM_005629.4:c.-5A>G

Variant names:

• chrX-153688570-A-G
• rs384573
• NM_005629.4:c.-5A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_005629.4(SLC6A8):​c.-5A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (37467 hom., 26651 hem., cov: 18)
  • Exomes 𝑓: 1.0 (312231 hom. 283695 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 2.25
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-153688570-A-G is Benign according to our data. Variant chrX-153688570-A-G is described in ClinVar as Benign. ClinVar VariationId is 130355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A8	NM_005629.4	c.-5A>G		5_prime_UTR_variant	Exon 1 of 13	ENST00000253122.10	NP_005620.1
SLC6A8	NM_001142805.2	c.-5A>G		5_prime_UTR_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.-5A>G		5_prime_UTR_variant	Exon 1 of 13	1	NM_005629.4	ENSP00000253122.5
PNCK	ENST00000458354.5	c.-3+245T>C		intron_variant	Intron 1 of 3	3		ENSP00000401542.1
PNCK	ENST00000480693.1	n.64+245T>C		intron_variant	Intron 1 of 3	5
SLC6A8	ENST00000476466.1	n.-153A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 1.00 AC: 101596 AN: 101596 Hom.: 37478 Cov.: 18

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 46799 AN: 46805 AF XY: 1.00

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 1.00 AC: 908179 AN: 908201 Hom.: 312231 Cov.: 17 AF XY: 1.00 AC XY: 283695 AN XY: 283695

African (AFR) AF: 1.00 AC: 18260 AN: 18260

American (AMR) AF: 1.00 AC: 15353 AN: 15357

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 13908 AN: 13908

East Asian (EAS) AF: 1.00 AC: 16577 AN: 16577

South Asian (SAS) AF: 1.00 AC: 38415 AN: 38416

European-Finnish (FIN) AF: 1.00 AC: 28559 AN: 28560

Middle Eastern (MID) AF: 1.00 AC: 2284 AN: 2284

European-Non Finnish (NFE) AF: 1.00 AC: 739086 AN: 739100

Other (OTH) AF: 1.00 AC: 35737 AN: 35739

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 1.00 AC: 101585 AN: 101585 Hom.: 37467 Cov.: 18 AF XY: 1.00 AC XY: 26651 AN XY: 26651

African (AFR) AF: 1.00 AC: 28352 AN: 28352

American (AMR) AF: 1.00 AC: 9955 AN: 9955

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2509 AN: 2509

East Asian (EAS) AF: 1.00 AC: 3063 AN: 3063

South Asian (SAS) AF: 1.00 AC: 2281 AN: 2281

European-Finnish (FIN) AF: 1.00 AC: 3800 AN: 3800

Middle Eastern (MID) AF: 1.00 AC: 195 AN: 195

European-Non Finnish (NFE) AF: 1.00 AC: 49434 AN: 49434

Other (OTH) AF: 1.00 AC: 1391 AN: 1391

Alfa AF: 1.00 Hom.: 5398

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 31, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 41. Only high quality variants are reported. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Creatine transporter deficiency Benign:3 Other:1

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 09-26-2019 by GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant. -

Creatine deficiency syndrome 1 Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SLC6A8-related disorder Benign:1

Jul 13, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.84
PhyloP100		2.3
PromoterAI		-0.028	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs384573; hg19: chrX-152954025; COSMIC: COSV108056444;