rs41307788

chr1-11045485-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS2

The NM_006610.4(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 NM_006610.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 7.79

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]

ACMG classification

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: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MASP2	NM_006610.4	c.467G>A	p.Cys156Tyr	missense_variant	4/11	ENST00000400897.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MASP2	ENST00000400897.8	c.467G>A	p.Cys156Tyr	missense_variant	4/11	1	NM_006610.4	P1

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 848 AN: 152118 Hom.: 1 Cov.: 33

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.: 7 AF XY: 0.00652 AC XY: 880 AN XY: 134972

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.: 66 Cov.: 31 AF XY: 0.00840 AC XY: 6103 AN XY: 726462

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.: 1 Cov.: 33 AF XY: 0.00492 AC XY: 366 AN XY: 74436

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.: 1

Bravo AF: 0.00552

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00636 AC: 771

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.00788

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency due to MASP-2 deficiency Uncertain:1 Benign: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 provided Benign:2

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	clinical testing	Invitae	Dec 31, 2019	- -

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	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.066	T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.4	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
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	T
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

Other links and lift over

dbSNP: rs41307788; hg19: chr1-11105542; COSMIC: COSV99071724; COSMIC: COSV99071724;