Genetic Variant MPP2:p.Arg500Pro (chr17-43877967-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005374.5(MPP2):c.1499G>C(p.Arg500Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,026 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R500Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MPP2
NM_005374.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.806

Publications

5 publications found

Variant links:

Genes affected

MPP2 (HGNC:7220): (MAGUK p55 scaffold protein 2) Palmitoylated membrane protein 2 is a member of a family of membrane-associated proteins termed MAGUKs (membrane-associated guanylate kinase homologs). MAGUKs interact with the cytoskeleton and regulate cell proliferation, signaling pathways, and intracellular junctions. Palmitoylated membrane protein 2 contains a conserved sequence, called the SH3 (src homology 3) motif, found in several other proteins that associate with the cytoskeleton and are suspected to play important roles in signal transduction. [provided by RefSeq, Jul 2008]

MPP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPP2	NM_005374.5 link	c.1499G>C	p.Arg500Pro	missense_variant	Exon 13 of 13	ENST00000269095.9	NP_005365.4	Q14168D3DX48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPP2	ENST00000269095.9 link	c.1499G>C	p.Arg500Pro	missense_variant	Exon 13 of 13	1	NM_005374.5	ENSP00000269095.4		D3DX48
MPP2	ENST00000461854.5 link	c.1571G>C	p.Arg524Pro	missense_variant	Exon 14 of 14	1		ENSP00000428286.1		D3DX49

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247806

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

6.84e-7

AC:

AN:

1461026

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726794

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111640

Other (OTH)

AF:

0.00

AC:

AN:

60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;.;.;.;T;.;.;.;.;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

D;.;.;D;D;D;D;D;.;D

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.81

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.7

D;D;D;.;.;.;D;D;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0050

D;D;D;.;.;.;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D;D;D;D;D;D;D

Vest4

0.53

MutPred

0.49

.;Loss of MoRF binding (P = 0.0719);.;Loss of MoRF binding (P = 0.0719);.;.;.;.;.;.;

MVP

0.72

MPC

1.8

ClinPred

0.88

GERP RS

4.2

gMVP

0.88

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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17-43877967-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over