rs374163604

Variant names:

• chrX-153693925-G-A
• rs374163604
• NM_005629.4:c.1162G>A

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.1162G>A (p.Ala388Thr) variant in SLC6A8 is a missense variant predicted to cause substitution of Threonine for Alanine at amino acid 338 (p.Ala338Thr). There is a ClinVar entry for this variant (Variation ID:436771). This variant is found with an allele frequency of 0.003854 in gnomADv2.1.1 with 17 hemizygotes present in that population database. Given the presence of >10 hemizygotes in gnomADv2.1.1 and an allele frequency >0.002, the stand alone benign criteria BA1 is applicable for this variant. 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 1.1.0; ; classification approved Feb 23, 2023): BA1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549443/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 8 hem., cov: 24)
  • Exomes 𝑓: 0.00048 (1 hom. 153 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:7
• Conservation: PhyloP100: 9.85
• Publications: 4 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]

SLC6A8 Gene-Disease associations (from GenCC):

• creatine transporter deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

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: 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.1162G>A	p.Ala388Thr	missense	Exon 8 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1132G>A	p.Ala378Thr	missense	Exon 8 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.817G>A	p.Ala273Thr	missense	Exon 8 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1162G>A	p.Ala388Thr	missense	Exon 8 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1162G>A	p.Ala388Thr	missense	Exon 8 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1162G>A	p.Ala388Thr	missense	Exon 8 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 34 AN: 112742 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000642

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000432

Gnomad OTH AF: 0.000657

GnomAD2 exomes AF: 0.000330 AC: 39 AN: 118182 AF XY: 0.000321

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: 0.00109

Gnomad NFE exome AF: 0.000547

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000479 AC: 504 AN: 1053227 Hom.: 1 Cov.: 32 AF XY: 0.000446 AC XY: 153 AN XY: 342745

African (AFR) AF: 0.00 AC: 0 AN: 25128

American (AMR) AF: 0.0000353 AC: 1 AN: 28368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18659

East Asian (EAS) AF: 0.00 AC: 0 AN: 27609

South Asian (SAS) AF: 0.0000200 AC: 1 AN: 50062

European-Finnish (FIN) AF: 0.000911 AC: 34 AN: 37308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2918

European-Non Finnish (NFE) AF: 0.000561 AC: 459 AN: 818837

Other (OTH) AF: 0.000203 AC: 9 AN: 44338

GnomAD4 genome AF: 0.000301 AC: 34 AN: 112795 Hom.: 0 Cov.: 24 AF XY: 0.000229 AC XY: 8 AN XY: 34941

African (AFR) AF: 0.0000964 AC: 3 AN: 31106

American (AMR) AF: 0.000278 AC: 3 AN: 10778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2759

European-Finnish (FIN) AF: 0.000642 AC: 4 AN: 6230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000432 AC: 23 AN: 53268

Other (OTH) AF: 0.000649 AC: 1 AN: 1542

Alfa AF: 0.000485 Hom.: 6

Bravo AF: 0.000234

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000453 AC: 3

ExAC AF: 0.0000943 AC: 10

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.020	D
Polyphen		0.97	D
Vest4		0.61
MVP		0.93
MPC		2.3
ClinPred		0.31	T
GERP RS		4.8
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.83
gMVP		0.82
Mutation Taster		=82/18	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: rs374163604; hg19: chrX-152959380;