rs199635059

Variant names:

• chrX-153694771-C-G
• rs199635059
• NM_005629.4:c.1649C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-153694771-C-G
• chrX-153694771-C-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005629.4(SLC6A8):​c.1649C>G​(p.Thr550Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,209,195 control chromosomes in the GnomAD database, including 2 homozygotes. There are 146 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T550T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., 17 hem., cov: 25)
  • Exomes 𝑓: 0.00032 (2 hom. 129 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.340
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07418674).
• BP6: Variant X-153694771-C-G is Benign according to our data. Variant chrX-153694771-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000323 (354/1096389) while in subpopulation MID AF = 0.00794 (29/3652). AF 95% confidence interval is 0.00568. There are 2 homozygotes in GnomAdExome4. There are 129 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 17 XL gene

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.1649C>G	p.Thr550Ser	missense	Exon 12 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.1619C>G	p.Thr540Ser	missense	Exon 12 of 13	NP_001136277.1
	SLC6A8	NM_001142806.1		c.1304C>G	p.Thr435Ser	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.1649C>G	p.Thr550Ser	missense	Exon 12 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.1646C>G	p.Thr549Ser	missense	Exon 12 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.1640C>G	p.Thr547Ser	missense	Exon 12 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 40 AN: 112755 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000360

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000296 AC: 54 AN: 182385 AF XY: 0.000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000456

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000323 AC: 354 AN: 1096389 Hom.: 2 Cov.: 38 AF XY: 0.000356 AC XY: 129 AN XY: 362153

African (AFR) AF: 0.000607 AC: 16 AN: 26355

American (AMR) AF: 0.000170 AC: 6 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.000462 AC: 25 AN: 54066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40330

Middle Eastern (MID) AF: 0.00794 AC: 29 AN: 3652

European-Non Finnish (NFE) AF: 0.000290 AC: 244 AN: 841217

Other (OTH) AF: 0.000739 AC: 34 AN: 46000

GnomAD4 genome AF: 0.000355 AC: 40 AN: 112806 Hom.: 0 Cov.: 25 AF XY: 0.000486 AC XY: 17 AN XY: 34978

African (AFR) AF: 0.000128 AC: 4 AN: 31137

American (AMR) AF: 0.00121 AC: 13 AN: 10773

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.000361 AC: 1 AN: 2769

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6247

Middle Eastern (MID) AF: 0.00913 AC: 2 AN: 219

European-Non Finnish (NFE) AF: 0.000376 AC: 20 AN: 53215

Other (OTH) AF: 0.00 AC: 0 AN: 1539

Alfa AF: 0.000651 Hom.: 5

Bravo AF: 0.000291

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000818

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Creatine transporter deficiency (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SLC6A8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.24	N
PhyloP100		0.34
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Benign	0.45	T
Sift4G	Benign	0.62	T
Polyphen		0.016	B
Vest4		0.095
MutPred		0.28		Loss of stability (P = 0.0855)
MVP		0.30
MPC		0.14
ClinPred		0.0047	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.39
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199635059; hg19: chrX-152960226;