X-153693483-C-A

Variant names:

• chrX-153693483-C-A
• NM_005629.4:c.1038C>A
• SLC6A8 p.Leu346Leu

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_005629.4(SLC6A8):​c.1038C>A​(p.Leu346Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. L346L) has been classified as Likely benign. The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC6A8 NM_005629.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.685
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P, Orphanet

ACMG classification

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20152795).
• BP7: Synonymous conserved (PhyloP=-0.685 with no splicing effect.

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.1038C>A	p.Leu346Leu	synonymous	Exon 7 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142806.1		c.693C>A	p.Leu231Leu	synonymous	Exon 7 of 13	NP_001136278.1	P48029-4
	SLC6A8	NM_001142805.2		c.1017-9C>A		intron	N/A	NP_001136277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.1038C>A	p.Leu346Leu	synonymous	Exon 7 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000457723.1	TSL:5	c.22C>A	p.His8Asn	missense	Exon 1 of 3	ENSP00000394742.1	H7C0F5
	SLC6A8	ENST00000955775.1		c.1038C>A	p.Leu346Leu	synonymous	Exon 7 of 13	ENSP00000625834.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.0
DANN	Benign	0.85
FATHMM_MKL	Benign	0.65	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.62	T
PhyloP100		-0.69
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.29
Sift4G	Benign	0.18	T
PromoterAI		-0.022	Neutral
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-152958938;