NM_005629.4:c.1218C>T

Variant names:

• chrX-153693981-C-T
• rs1557045310
• NM_005629.4:c.1218C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_005629.4(SLC6A8):​c.1218C>T​(p.Phe406Phe) 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.12
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23427719).
• BP6: Variant X-153693981-C-T is Benign according to our data. Variant chrX-153693981-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 465143.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.12 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.1218C>T	p.Phe406Phe	synonymous	Exon 8 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1188C>T	p.Phe396Phe	synonymous	Exon 8 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.873C>T	p.Phe291Phe	synonymous	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.1218C>T	p.Phe406Phe	synonymous	Exon 8 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000457723.1	TSL:5	c.202C>T	p.Leu68Phe	missense	Exon 2 of 3	ENSP00000394742.1	H7C0F5
	SLC6A8	ENST00000955775.1		c.1218C>T	p.Phe406Phe	synonymous	Exon 8 of 13	ENSP00000625834.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 134581 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.38e-7 AC: 1 AN: 1066113 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 346029

African (AFR) AF: 0.00 AC: 0 AN: 25755

American (AMR) AF: 0.00 AC: 0 AN: 30426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18847

East Asian (EAS) AF: 0.00 AC: 0 AN: 28706

South Asian (SAS) AF: 0.00 AC: 0 AN: 51043

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38103

Middle Eastern (MID) AF: 0.000319 AC: 1 AN: 3137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825223

Other (OTH) AF: 0.00 AC: 0 AN: 44873

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Creatine transporter deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.95
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.87	T
PhyloP100		2.1
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.11
MutPred		0.18		Gain of loop (P = 0.069)
MVP		0.73
ClinPred		0.28	T
GERP RS		3.0
Mutation Taster		=93/7	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: rs1557045310; hg19: chrX-152959436;