Genetic Variant NM_005629.4:c.780C>T (chrX-153693043-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005629.4(SLC6A8):c.780C>T(p.Ile260Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,209,720 control chromosomes in the GnomAD database, including 1 homozygotes. There are 118 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). The gene SLC6A8 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., 53 hem., cov: 25)

Exomes 𝑓: 0.00019 ( 0 hom. 65 hem. )

Consequence

SLC6A8
NM_005629.4 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.959

Publications

0 publications found

Variant links:

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

SLC6A8 links:

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ACMG classification

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

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant X-153693043-C-T is Benign according to our data. Variant chrX-153693043-C-T is described in ClinVar as Benign. ClinVar VariationId is 383165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.959 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00168 (190/112892) while in subpopulation AFR AF = 0.00584 (182/31163). AF 95% confidence interval is 0.00515. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 53 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	NM_005629.4	MANE Select	c.780C>T	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	NP_005620.1	P48029-1
SLC6A8	NM_001142805.2		c.780C>T	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	NP_001136277.1
SLC6A8	NM_001142806.1		c.435C>T	p.Ile145Ile	splice_region synonymous	Exon 5 of 13	NP_001136278.1	P48029-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.780C>T	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	ENSP00000253122.5	P48029-1
SLC6A8	ENST00000955775.1		c.780C>T	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	ENSP00000625834.1
SLC6A8	ENST00000922630.1		c.780C>T	p.Ile260Ile	splice_region synonymous	Exon 5 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

190

AN:

112838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00585

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000464

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00198

GnomAD2 exomes

AF:

0.000428

AC:

AN:

182298

AF XY:

0.000401

show subpopulations

Gnomad AFR exome

AF:

0.00482

Gnomad AMR exome

AF:

0.000438

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:

0.000445

GnomAD4 exome

AF:

0.000190

AC:

208

AN:

1096828

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

362786

show subpopulations

African (AFR)

AF:

0.00565

AC:

149

AN:

26367

American (AMR)

AF:

0.000511

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19379

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54085

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40431

Middle Eastern (MID)

AF:

0.000296

AC:

AN:

3380

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

841794

Other (OTH)

AF:

0.000565

AC:

AN:

45998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00168

AC:

190

AN:

112892

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

AN XY:

35072

show subpopulations

African (AFR)

AF:

0.00584

AC:

182

AN:

31163

American (AMR)

AF:

0.000463

AC:

AN:

10800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

2772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53232

Other (OTH)

AF:

0.00196

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.00200

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Creatine transporter deficiency (1)

Inborn genetic diseases (1)

SLC6A8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.7

(source)

DANN

Benign

0.89

PhyloP100

-0.96

PromoterAI

-0.0072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over