10-52771482-G-A

Variant names:

Variant summary

Our verdict is . The variant received -4 ACMG points: 4P and 8B. PS3BA1

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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000914462: 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. PMID:22383712".

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 Gene-Disease associations (from GenCC):

mannose-binding lectin deficiency
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

MBL2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001378373.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000914462: 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. PMID:22383712

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378373.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MBL2	NM_001378373.1	MANE Select	c.154C>T	p.Arg52Cys	missense	Exon 2 of 5	NP_001365302.1	P11226
MBL2	NM_000242.3		c.154C>T	p.Arg52Cys	missense	Exon 1 of 4	NP_000233.1	P11226
MBL2	NM_001378374.1		c.154C>T	p.Arg52Cys	missense	Exon 2 of 5	NP_001365303.1	P11226

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MBL2	ENST00000674931.1	MANE Select	c.154C>T	p.Arg52Cys	missense	Exon 2 of 5	ENSP00000502789.1	P11226
MBL2	ENST00000373968.3	TSL:1	c.154C>T	p.Arg52Cys	missense	Exon 1 of 4	ENSP00000363079.3	P11226
MBL2	ENST00000675947.1		c.154C>T	p.Arg52Cys	missense	Exon 2 of 5	ENSP00000502615.1	P11226

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

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0689

EpiControl

AF:

0.0747

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mannose-binding lectin deficiency (4)

not provided (2)

Cystic fibrosis (1)

Computational scores

Source: dbNSFP v4.9

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

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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