rs782694291

Variant names:

• chrX-153693184-G-A
• rs782694291
• NM_005629.4:c.912+9G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-153693184-G-A
• chrX-153693184-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.912+9G>A variant in SLC6A8 is in the region of the donor splice site of intron 5. The highest population minor allele frequency in gnomAD v2.1.1 is 0.004083 in the Latino/Admixed American population, meeting the ClinGen CCDS VCEP allele frequency threshold for BS1 (>0.0002) (BS1). The variant is present in 25 hemizygotes and 2 homozygotes in gnomAD v2.1.1 (BS2). The computational predictor, SpliceAI, predicts that the variant has no impact on splicing, and varSEAK indicates an unknown effect on splicing due to possible strengthening of a cryptic splice site in intron 5. To our knowledge, this variant has not been reported in any patients with features of creatine transporter deficiency the literature and no results of functional or splicing assays are unavailable. There is a ClinVar entry for this variant (Variation ID: 383888). In summary, this variant meets the criteria to be classified as benign for creatine transporter deficiency. SLC6A8-specific ACMG-AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BS1, BS2.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549344/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.000097 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.00011 (2 hom. 26 hem.)
• Consequence: SLC6A8 NM_005629.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -0.0590
• Publications: 1 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

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

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.912+9G>A		intron	N/A	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.912+9G>A		intron	N/A	NP_001136277.1
	SLC6A8	NM_001142806.1		c.567+9G>A		intron	N/A	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.912+9G>A		intron	N/A	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.912+9G>A		intron	N/A	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.912+9G>A		intron	N/A	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.0000974 AC: 11 AN: 112907 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

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: 0.000619 AC: 112 AN: 181006 AF XY: 0.000362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00410

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: 0.000112 AC: 123 AN: 1097043 Hom.: 2 Cov.: 32 AF XY: 0.0000717 AC XY: 26 AN XY: 362635

African (AFR) AF: 0.00 AC: 0 AN: 26375

American (AMR) AF: 0.00344 AC: 121 AN: 35171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54087

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3811

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841563

Other (OTH) AF: 0.0000435 AC: 2 AN: 46010

GnomAD4 genome AF: 0.0000974 AC: 11 AN: 112907 Hom.: 0 Cov.: 24 AF XY: 0.000143 AC XY: 5 AN XY: 35049

African (AFR) AF: 0.00 AC: 0 AN: 31120

American (AMR) AF: 0.00102 AC: 11 AN: 10802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2785

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6279

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53237

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000253

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Creatine transporter deficiency (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.84
DANN	Benign	0.82
PhyloP100		-0.059
PromoterAI		0.0054	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782694291; hg19: chrX-152958639; COSMIC: COSV109411241; COSMIC: COSV109411241;