chrX-153694749-G-C

Variant names:

• chrX-153694749-G-C
• rs782028471
• NM_005629.4:c.1627G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_005629.4(SLC6A8):​c.1627G>C​(p.Glu543Gln) variant causes a missense 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. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E543K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.537
• 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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant X-153694749-G-C is Benign according to our data. Variant chrX-153694749-G-C is described in ClinVar as Benign. ClinVar VariationId is 1169766.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1627G>C	p.Glu543Gln	missense	Exon 12 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1597G>C	p.Glu533Gln	missense	Exon 12 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1282G>C	p.Glu428Gln	missense	Exon 12 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.1627G>C	p.Glu543Gln	missense	Exon 12 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1624G>C	p.Glu542Gln	missense	Exon 12 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1618G>C	p.Glu540Gln	missense	Exon 12 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182609 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.00000273 AC: 3 AN: 1097214 Hom.: 0 Cov.: 38 AF XY: 0.00000551 AC XY: 2 AN XY: 362958

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26374

American (AMR) AF: 0.0000284 AC: 1 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54097

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841902

Other (OTH) AF: 0.00 AC: 0 AN: 46028

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 25

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: 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	Benign	0.070
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.0
DANN	Benign	0.58
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.010	N
PhyloP100		0.54
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.13
Sift	Benign	0.22	T
Sift4G	Benign	0.53	T
Polyphen		0.012	B
Vest4		0.057
MutPred		0.37		Loss of sheet (P = 0.1907)
MVP		0.39
MPC		0.16
ClinPred		0.057	T
GERP RS		-6.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.64
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782028471; hg19: chrX-152960204;