rs34776397

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378778.1(MPDZ):c.2602G>A(p.Gly868Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,611,424 control chromosomes in the GnomAD database, including 29 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G868G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0069 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 12 hom. )

Consequence

MPDZ
NM_001378778.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.75

Publications

1 publications found

Variant links:

Genes affected

MPDZ (HGNC:7208): (multiple PDZ domain crumbs cell polarity complex component) The protein encoded by this gene has multiple PDZ domains, which are hallmarks of protein-protein interactions. The encoded protein is known to interact with the HTR2C receptor and may cause it to clump at the cell surface. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

MPDZ Gene-Disease associations (from GenCC):

hydrocephalus, nonsyndromic, autosomal recessive 2
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

MPDZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016598701).

BP6

Variant 9-13183465-C-T is Benign according to our data. Variant chr9-13183465-C-T is described in ClinVar as Benign. ClinVar VariationId is 211511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00692 (1052/151970) while in subpopulation AFR AF = 0.0245 (1018/41506). AF 95% confidence interval is 0.0233. There are 17 homozygotes in GnomAd4. There are 438 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDZ	NM_001378778.1 link	c.2602G>A	p.Gly868Ser	missense_variant	Exon 19 of 47	ENST00000319217.12	NP_001365707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPDZ	ENST00000319217.12 link	c.2602G>A	p.Gly868Ser	missense_variant	Exon 19 of 47	5	NM_001378778.1	ENSP00000320006.7

Frequencies

GnomAD3 genomes

AF:

0.00691

AC:

1049

AN:

151852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00184

AC:

454

AN:

246850

AF XY:

0.00133

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000564

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000751

AC:

1096

AN:

1459454

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

488

AN XY:

725986

show subpopulations

African (AFR)

AF:

0.0281

AC:

937

AN:

33328

American (AMR)

AF:

0.00101

AC:

AN:

44478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39478

South Asian (SAS)

AF:

0.0000581

AC:

AN:

86034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1110710

Other (OTH)

AF:

0.00158

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00692

AC:

1052

AN:

151970

Hom.:

Cov.:

AF XY:

0.00590

AC XY:

438

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.0245

AC:

1018

AN:

41506

American (AMR)

AF:

0.00158

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67896

Other (OTH)

AF:

0.00285

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00194

Hom.:

Bravo

AF:

0.00846

ESP6500AA

AF:

0.0243

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00240

AC:

290

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.016

T;.;.;.;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.055

LIST_S2

Uncertain

0.86

D;D;D;D;.;D

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-2.1

N;N;N;N;N;.

PhyloP100

1.8

PrimateAI

Benign

0.30

PROVEAN

Benign

0.74

N;N;N;N;N;N

REVEL

Benign

0.025

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

.;B;B;.;B;.

Vest4

0.13

MVP

0.092

ClinPred

0.00090

GERP RS

0.69

Varity_R

0.023

gMVP

0.23

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over