rs5030737

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001378373.1(MBL2):c.154C>T(p.Arg52Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,613,662 control chromosomes in the GnomAD database, including 3,819 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 0.049 ( 282 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3537 hom. )

Consequence

MBL2
NM_001378373.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:3O:1

Conservation

PhyloP100: 0.972

Publications

266 publications found

Variant links:

Genes affected

MBL2 (HGNC:6922): (mannose binding lectin 2) This gene encodes the soluble mannose-binding lectin or mannose-binding protein found in serum. The protein encoded belongs to the collectin family and is an important element in the innate immune system. The protein recognizes and binds to mannose and N-acetylglucosamine on many microorganisms, including bacteria, yeast, and viruses including influenza virus, HIV and SARS-CoV. This binding activates the classical complement pathway. Deficiencies of this gene have been associated with susceptibility to autoimmune and infectious diseases. [provided by RefSeq, Jun 2020]

MBL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030004382).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MBL2	NM_001378373.1 link	c.154C>T	p.Arg52Cys	missense_variant	Exon 2 of 5	ENST00000674931.1	NP_001365302.1
MBL2	NM_000242.3 link	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 4		NP_000233.1
MBL2	NM_001378374.1 link	c.154C>T	p.Arg52Cys	missense_variant	Exon 2 of 5		NP_001365303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MBL2	ENST00000674931.1 link	c.154C>T	p.Arg52Cys	missense_variant	Exon 2 of 5		NM_001378373.1	ENSP00000502789.1
MBL2	ENST00000373968.3 link	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 4	1		ENSP00000363079.3
MBL2	ENST00000675947.1 link	c.154C>T	p.Arg52Cys	missense_variant	Exon 2 of 5			ENSP00000502615.1

Frequencies

GnomAD3 genomes

AF:

0.0494

AC:

7514

AN:

152044

Hom.:

282

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.0388

Gnomad ASJ

AF:

0.0991

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0567

Gnomad FIN

AF:

0.0609

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0722

Gnomad OTH

AF:

0.0503

GnomAD2 exomes

AF:

0.0556

AC:

13955

AN:

251104

AF XY:

0.0585

show subpopulations

Gnomad AFR exome

AF:

0.0107

Gnomad AMR exome

AF:

0.0255

Gnomad ASJ exome

AF:

0.103

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0580

Gnomad NFE exome

AF:

0.0736

Gnomad OTH exome

AF:

0.0559

GnomAD4 exome

AF:

0.0659

AC:

96331

AN:

1461500

Hom.:

3537

Cov.:

AF XY:

0.0665

AC XY:

48339

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.00992

AC:

332

AN:

33472

American (AMR)

AF:

0.0272

AC:

1218

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

2711

AN:

26110

East Asian (EAS)

AF:

0.000202

AC:

AN:

39698

South Asian (SAS)

AF:

0.0602

AC:

5193

AN:

86242

European-Finnish (FIN)

AF:

0.0576

AC:

3077

AN:

53420

Middle Eastern (MID)

AF:

0.0735

AC:

422

AN:

5744

European-Non Finnish (NFE)

AF:

0.0717

AC:

79674

AN:

1111726

Other (OTH)

AF:

0.0612

AC:

3696

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4355

8710

13065

17420

21775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2890

5780

8670

11560

14450

<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:

0.0494

AC:

7513

AN:

152162

Hom.:

282

Cov.:

AF XY:

0.0486

AC XY:

3613

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0118

AC:

491

AN:

41520

American (AMR)

AF:

0.0387

AC:

592

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0991

AC:

343

AN:

3460

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0567

AC:

274

AN:

4830

European-Finnish (FIN)

AF:

0.0609

AC:

644

AN:

10578

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0722

AC:

4912

AN:

68006

Other (OTH)

AF:

0.0498

AC:

105

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

350

700

1050

1400

1750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0629

Hom.:

1489

Bravo

AF:

0.0463

TwinsUK

AF:

0.0690

AC:

256

ALSPAC

AF:

0.0714

AC:

275

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.0693

AC:

596

ExAC

AF:

0.0570

AC:

6914

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0689

EpiControl

AF:

0.0747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mannose-binding lectin deficiency

Pathogenic:2Benign:2

Dec 11, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MLB2 c.154C>T (p.Arg52Cys) missense variant, commonly referred to as the "D" allele, has been described in at least one study in individuals with recurrent infections and low serum MBP levels in which it was found in a compound heterozygous state with another missense variant in one individual with a very low serum MBP level and in a homozygous state in another individual with no detectable serum MBP level (Summerfield et al. 1995). The p.Arg52Cys variant has also been investigated in healthy unrelated individuals with low or undetectable MBP levels (Madsen et al. 1994; Babovic-Vuksanovic et al. 1999) and found at a frequency of 0.05 in both the African and Caucasian populations in both a compound heterozygous state and a heterozygous state. Functional studies by Liu et al. (2012) showed that the p.Arg52Cys variant did not affect gene transcription or protein secretion, but did result in a lower level of oligomerization, a loss of ability to bind mannan, a reduced ability to bind to MASP1 and MASP2 and failed to activate the complement system. However, it should be noted that MBL deficiency is very common. The p.Arg52Cys variant is reported at a frequency of is 0.11111 in the Finnish population of the 1000 Genomes Project. While the allele frequency for this variant appears to be high, multiple studies referenced in this paragraph have shown a significant over-representation of this variant in individuals with low levels of mannose-binding lectin as compared to controls. Many individuals who carry MBL2 variants classified as pathogenic do not develop clinical complications. Based on the evidence, the p.Arg52Cys variant is classified as pathogenic for mannose-binding lectin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Aug 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:1Benign:1

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cystic fibrosis

Other:1

Apr 01, 2019

Center for Computational Genomics and Data Science, University of Alabama

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.091

LIST_S2

Pathogenic

0.97

MetaRNN

Benign

0.0030

MetaSVM

Uncertain

0.062

MutationAssessor

Pathogenic

3.4

PhyloP100

0.97

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.091

MPC

0.50

ClinPred

0.067

GERP RS

3.1

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.59

gMVP

0.42

Mutation Taster

=85/15

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over