rs761334309

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_016034.5(MRPS2):c.328C>T(p.Arg110Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,613,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

MRPS2
NM_016034.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.06

Variant links:

Genes affected

MRPS2 (HGNC:14495): (mitochondrial ribosomal protein S2) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S2 family. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

MRPS2 links:

ENSG00000226706 (HGNC:):

ENSG00000226706 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

PP5

Variant 9-135503570-C-T is Pathogenic according to our data. Variant chr9-135503570-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 523223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-135503570-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS2	NM_016034.5 link	c.328C>T	p.Arg110Cys	missense_variant	Exon 4 of 4	ENST00000241600.10	NP_057118.1	Q9Y399

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS2	ENST00000241600.10 link	c.328C>T	p.Arg110Cys	missense_variant	Exon 4 of 4	1	NM_016034.5	ENSP00000241600.5		Q9Y399

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250148

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135358

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461316

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency 36

Pathogenic:3

Nov 13, 2020

Laboratory of Biochemistry, Assistance Publique Hopitaux de Paris - Bicetre Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg110Cys variant in MRPS2 has been reported in 2 patients (one in heterozygous compound state and one in homozygous state). Mitochondrial respiratory chain complexes (I and IV) deficiencies were found in both patients. Typical clinical features of mitochondrial disorders (hyperlactatemia, hypoglycemia, hearing loss, neurological abnormaliites). The Arg110Cys variant fulfils the criteria to be classified as pathogenic on the basis of segregation studies, absence in controls and functional evidence. -

May 03, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Pathogenic, for Combined oxidative phosphorylation deficiency 36, autosomal recessive. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3-Very Strong => PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/29576219). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;D;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

4.2

H;H;.

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.7

D;D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.89

MVP

0.66

MPC

0.99

ClinPred

1.0

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.92

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over