NM_005629.4:c.70G>C

Variant names:

• chrX-153688644-G-C
• rs1557043775
• NM_005629.4:c.70G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_005629.4(SLC6A8):c.70G>C (p.Ala24Pro) variant in SLC6A8 is a missense variant predicted to cause substitution of Alanine for Proline at amino acid 24 (p.Ala24Pro). In gnomAD v2.1.1, the highest population minor allele frequency is 0.0000159 (1/62731 alleles) in the European population, with no hemi- or homozygotes, which is <0.0002 therefore PM2_Supporting criteria applicable. The computational predictor REVEL gives a score of 0.085 which is below the threshold of 0.25, and does not predict a damaging effect on SLC6A8 function (BP4). To our knowledge, this variant has not been previously reported in affected individuals in the literature. There is a ClinVar entry for this variant (Variation ID: 465148). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Creatine Transporter Deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA415076119/MONDO:0010305/027

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: SLC6A8 NM_005629.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 0.554
• 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]

PNCK (HGNC:13415): (pregnancy up-regulated nonubiquitous CaM kinase) PNCK is a member of the calcium/calmodulin-dependent protein kinase family of protein serine/threonine kinases (see CAMK1; MIM 604998) (Gardner et al., 2000 [PubMed 10673339]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

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.70G>C	p.Ala24Pro	missense	Exon 1 of 13	NP_005620.1	P48029-1
	SLC6A8	NM_001142805.2		c.70G>C	p.Ala24Pro	missense	Exon 1 of 13	NP_001136277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A8	ENST00000253122.10	TSL:1 MANE Select	c.70G>C	p.Ala24Pro	missense	Exon 1 of 13	ENSP00000253122.5	P48029-1
	SLC6A8	ENST00000955775.1		c.70G>C	p.Ala24Pro	missense	Exon 1 of 13	ENSP00000625834.1
	SLC6A8	ENST00000922630.1		c.70G>C	p.Ala24Pro	missense	Exon 1 of 13	ENSP00000592689.1

Frequencies

GnomAD3 genomes AF: 0.00000930 AC: 1 AN: 107560 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000957

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: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 1 AN: 62731 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000861

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 AF: 0.00000103 AC: 1 AN: 970401 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 309501

African (AFR) AF: 0.00 AC: 0 AN: 19982

American (AMR) AF: 0.0000510 AC: 1 AN: 19625

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15898

East Asian (EAS) AF: 0.00 AC: 0 AN: 19761

South Asian (SAS) AF: 0.00 AC: 0 AN: 43627

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 775188

Other (OTH) AF: 0.00 AC: 0 AN: 39557

GnomAD4 genome AF: 0.00000930 AC: 1 AN: 107565 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 31027

African (AFR) AF: 0.00 AC: 0 AN: 30037

American (AMR) AF: 0.0000956 AC: 1 AN: 10457

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2594

East Asian (EAS) AF: 0.00 AC: 0 AN: 3290

South Asian (SAS) AF: 0.00 AC: 0 AN: 2536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51277

Other (OTH) AF: 0.00 AC: 0 AN: 1488

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Creatine transporter deficiency (2)
-	1	-	Creatine deficiency syndrome 1 (1)
-	1	-	SLC6A8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.55
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.085
Sift	Benign	0.31	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.27		Gain of catalytic residue at A24 (P = 0.0186)
MVP		0.10
MPC		1.5
ClinPred		0.028	T
GERP RS		2.6
PromoterAI		-0.00060	Neutral
Varity_R		0.082
gMVP		0.32
Mutation Taster		=97/3	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: rs1557043775; hg19: chrX-152954099;