NM_005629.4:c.1016+9C>T

Variant names:

• chrX-153693375-C-T
• rs190690083
• NM_005629.4:c.1016+9C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4:c.1016+9C>T variant in SLC6A8 is an intronic variant in the region of the donor splice site of intron 6. The total number of hemizygotes in gnomAD v2.1.1 is 46, meeting the ClinGen CCDS VCEP’s threshold for BA1 (>10 hemizygotes). The highest minor allele frequency is 0.0009212 (European non-Finnish) with 39 hemizygotes in that population (BA1). The computational predictors SpliceAI and varSEAK predict that the variant has no impact in splicing (BP4). There is a ClinVar entry for the variant (Variation ID: 379398). 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): BA1, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10549374/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., 21 hem., cov: 24)
  • Exomes 𝑓: 0.00072 (1 hom. 252 hem.)
• Consequence: SLC6A8 NM_005629.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -0.149
• 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]

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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1016+9C>T		intron	N/A	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1016+9C>T		intron	N/A	NP_001136277.1
	SLC6A8	NM_001142806.1		c.671+9C>T		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.1016+9C>T		intron	N/A	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1016+9C>T		intron	N/A	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1016+9C>T		intron	N/A	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.000472 AC: 53 AN: 112206 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000827

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000558 AC: 102 AN: 182927 AF XY: 0.000620

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00100

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000716 AC: 782 AN: 1091882 Hom.: 1 Cov.: 31 AF XY: 0.000705 AC XY: 252 AN XY: 357570

African (AFR) AF: 0.000114 AC: 3 AN: 26298

American (AMR) AF: 0.0000852 AC: 3 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19348

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53982

European-Finnish (FIN) AF: 0.00124 AC: 50 AN: 40482

Middle Eastern (MID) AF: 0.000731 AC: 3 AN: 4102

European-Non Finnish (NFE) AF: 0.000833 AC: 697 AN: 836415

Other (OTH) AF: 0.000523 AC: 24 AN: 45877

GnomAD4 genome AF: 0.000472 AC: 53 AN: 112258 Hom.: 0 Cov.: 24 AF XY: 0.000610 AC XY: 21 AN XY: 34444

African (AFR) AF: 0.000162 AC: 5 AN: 30785

American (AMR) AF: 0.000187 AC: 2 AN: 10692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3553

South Asian (SAS) AF: 0.00 AC: 0 AN: 2728

European-Finnish (FIN) AF: 0.000321 AC: 2 AN: 6229

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000827 AC: 44 AN: 53187

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.000434 Hom.: 3

Bravo AF: 0.000491

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Creatine transporter deficiency (2)
-	-	1	not specified (1)
-	-	1	SLC6A8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.53
PhyloP100		-0.15
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs190690083; hg19: chrX-152958830;