rs5030737

Positions:

Variant summary

Our verdict is Benign. Variant got -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:2O:1

Conservation

PhyloP100: 0.972

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE
MBL2	NM_001378373.1 linkuse as main transcript	c.154C>T	p.Arg52Cys	missense_variant	2/5	ENST00000674931.1
MBL2	NM_000242.3 linkuse as main transcript	c.154C>T	p.Arg52Cys	missense_variant	1/4
MBL2	NM_001378374.1 linkuse as main transcript	c.154C>T	p.Arg52Cys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MBL2	ENST00000674931.1 linkuse as main transcript	c.154C>T	p.Arg52Cys	missense_variant	2/5		NM_001378373.1	P1
MBL2	ENST00000373968.3 linkuse as main transcript	c.154C>T	p.Arg52Cys	missense_variant	1/4	1		P1
MBL2	ENST00000675947.1 linkuse as main transcript	c.154C>T	p.Arg52Cys	missense_variant	2/5			P1

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

GnomAD3 exomes

AF:

0.0556

AC:

13955

AN:

251104

Hom.:

532

AF XY:

0.0585

AC XY:

7933

AN XY:

135706

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 SAS exome

AF:

0.0623

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

Gnomad4 AFR exome

AF:

0.00992

Gnomad4 AMR exome

AF:

0.0272

Gnomad4 ASJ exome

AF:

0.104

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0602

Gnomad4 FIN exome

AF:

0.0576

Gnomad4 NFE exome

AF:

0.0717

Gnomad4 OTH exome

AF:

0.0612

GnomAD4 genome

AF:

0.0494

AC:

7513

AN:

152162

Hom.:

282

Cov.:

AF XY:

0.0486

AC XY:

3613

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0118

Gnomad4 AMR

AF:

0.0387

Gnomad4 ASJ

AF:

0.0991

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0567

Gnomad4 FIN

AF:

0.0609

Gnomad4 NFE

AF:

0.0722

Gnomad4 OTH

AF:

0.0498

Alfa

AF:

0.0654

Hom.:

796

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:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mannose-binding lectin deficiency

Pathogenic:2Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2018	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. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Cystic fibrosis

Other:1

risk factor, no assertion criteria provided

research

Center for Computational Genomics and Data Science, University of Alabama

Apr 01, 2019

- -

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

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

MutationTaster

Benign

0.99

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

Varity_R

0.59

gMVP

0.42

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