chr1-11045485-C-T

Position:

chr1-11045485-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2

The ENST00000400897.8(MASP2):c.467G>A(p.Cys156Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00814 in 1,612,448 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0056 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 66 hom. )

Consequence

MASP2
ENST00000400897.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 7.79

Variant links:

Genes affected

MASP2 (HGNC:6902): (MBL associated serine protease 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is proteolytically processed to generate A and B chains that heterodimerize to form the mature protease. This protease cleaves complement components C2 and C4 in order to generate C3 convertase in the lectin pathway of the complement system. The encoded protease also plays a role in the coagulation cascade through cleavage of prothrombin to form thrombin. Myocardial infarction and acute stroke patients exhibit reduced serum concentrations of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

MASP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.06558162).

BP6

Variant 1-11045485-C-T is Benign according to our data. Variant chr1-11045485-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 291802.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=4}.

BS2

High Homozygotes in GnomAdExome4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASP2	NM_006610.4 linkuse as main transcript	c.467G>A	p.Cys156Tyr	missense_variant	4/11	ENST00000400897.8	NP_006601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASP2	ENST00000400897.8 linkuse as main transcript	c.467G>A	p.Cys156Tyr	missense_variant	4/11	1	NM_006610.4	ENSP00000383690	P1	O00187-1

Frequencies

GnomAD3 genomes

AF:

0.00557

AC:

848

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00919

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00597

AC:

1484

AN:

248664

Hom.:

AF XY:

0.00652

AC XY:

880

AN XY:

134972

show subpopulations

Gnomad AFR exome

AF:

0.00169

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00522

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00735

Gnomad FIN exome

AF:

0.00334

Gnomad NFE exome

AF:

0.00905

Gnomad OTH exome

AF:

0.00543

GnomAD4 exome

AF:

0.00841

AC:

12277

AN:

1460212

Hom.:

Cov.:

AF XY:

0.00840

AC XY:

6103

AN XY:

726462

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00517

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00710

Gnomad4 FIN exome

AF:

0.00359

Gnomad4 NFE exome

AF:

0.00963

Gnomad4 OTH exome

AF:

0.00838

GnomAD4 genome

AF:

0.00556

AC:

847

AN:

152236

Hom.:

Cov.:

AF XY:

0.00492

AC XY:

366

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00540

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00918

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00770

Hom.:

Bravo

AF:

0.00552

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00965

AC:

ExAC

AF:

0.00636

AC:

771

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.00788

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MASP2: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Immunodeficiency due to MASP-2 deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.C156Y in MASP2 (NM_006610.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.C156Y variant has a GnomAD frequency of 0.5878 %. There is a large physicochemical difference between cysteine and tyrosine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.C156Y missense variant is predicted to be damaging by both SIFT and PolyPhen2. The cysteine residue at codon 156 of MASP2 is conserved in all mammalian species. The nucleotide c.467 in MASP2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant detected in unspecified number of cases with atypical hemolytic uremic syndrome (Bu 2014). MAF 1.2%. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.066

T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

4.4

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-10

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.95

MPC

0.33

ClinPred

0.12

GERP RS

4.2

Varity_R

0.98

gMVP

0.89

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