NM_006610.4:c.359A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4_StrongBS1_SupportingBS2

The NM_006610.4(MASP2):c.359A>G(p.Asp120Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,613,734 control chromosomes in the GnomAD database, including 701 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 0.022 ( 51 hom., cov: 33)

Exomes 𝑓: 0.027 ( 650 hom. )

Consequence

MASP2
NM_006610.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2B:3

Conservation

PhyloP100: 7.73

Publications

66 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency due to MASP-2 deficiency
Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine

MASP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

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

BP4

Computational evidence support a benign effect (MetaRNN=0.010086238).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3368/152328) while in subpopulation NFE AF = 0.0324 (2204/68018). AF 95% confidence interval is 0.0313. There are 51 homozygotes in GnomAd4. There are 1693 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 51 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006610.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP2	NM_006610.4	MANE Select	c.359A>G	p.Asp120Gly	missense	Exon 3 of 11	NP_006601.2
	MASP2	NM_139208.3		c.359A>G	p.Asp120Gly	missense	Exon 3 of 5	NP_631947.1	O00187-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MASP2	ENST00000400897.8	TSL:1 MANE Select	c.359A>G	p.Asp120Gly	missense	Exon 3 of 11	ENSP00000383690.3	O00187-1
MASP2	ENST00000400898.3	TSL:1	c.359A>G	p.Asp120Gly	missense	Exon 3 of 5	ENSP00000383691.3	O00187-2
MASP2	ENST00000480221.1	TSL:1	n.379A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0221

AC:

3370

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00543

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0205

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0505

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0324

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.0214

AC:

5366

AN:

250710

AF XY:

0.0212

show subpopulations

Gnomad AFR exome

AF:

0.00438

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0471

Gnomad NFE exome

AF:

0.0323

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0270

AC:

39418

AN:

1461406

Hom.:

650

Cov.:

AF XY:

0.0264

AC XY:

19204

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.00364

AC:

122

AN:

33480

American (AMR)

AF:

0.0106

AC:

475

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00423

AC:

365

AN:

86250

European-Finnish (FIN)

AF:

0.0463

AC:

2453

AN:

52998

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0310

AC:

34458

AN:

1111964

Other (OTH)

AF:

0.0237

AC:

1432

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2352

4704

7056

9408

11760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1216

2432

3648

4864

6080

<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:

0.0221

AC:

3368

AN:

152328

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

1693

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00541

AC:

225

AN:

41588

American (AMR)

AF:

0.0205

AC:

314

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0505

AC:

536

AN:

10618

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0324

AC:

2204

AN:

68018

Other (OTH)

AF:

0.0208

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

184

368

553

737

921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0285

Hom.:

138

Bravo

AF:

0.0189

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0288

AC:

248

ExAC

AF:

0.0222

AC:

2692

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0265

EpiControl

AF:

0.0268

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency due to MASP-2 deficiency (5)

not specified (2)

MASP2-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.38

MutationAssessor

Pathogenic

3.6

PhyloP100

7.7

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.32

MPC

0.29

ClinPred

0.052

GERP RS

4.8

Varity_R

0.95

gMVP

0.87

Mutation Taster

=44/56

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over