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rs5030737

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

5
6
7

Clinical Significance

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

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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 UniProt
MBL2NM_001378373.1 linkuse as main transcriptc.154C>T p.Arg52Cys missense_variant 2/5 ENST00000674931.1
MBL2NM_000242.3 linkuse as main transcriptc.154C>T p.Arg52Cys missense_variant 1/4
MBL2NM_001378374.1 linkuse as main transcriptc.154C>T p.Arg52Cys missense_variant 2/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MBL2ENST00000674931.1 linkuse as main transcriptc.154C>T p.Arg52Cys missense_variant 2/5 NM_001378373.1 P1
MBL2ENST00000373968.3 linkuse as main transcriptc.154C>T p.Arg52Cys missense_variant 1/41 P1
MBL2ENST00000675947.1 linkuse as main transcriptc.154C>T p.Arg52Cys missense_variant 2/5 P1

Frequencies

GnomAD3 genomes
AF:
0.0494
AC:
7514
AN:
152044
Hom.:
282
Cov.:
32
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.:
33
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.:
32
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:
52
ESP6500EA
AF:
0.0693
AC:
596
ExAC
AF:
0.0570
AC:
6914
Asia WGS
AF:
0.0250
AC:
87
AN:
3478
EpiCase
AF:
0.0689
EpiControl
AF:
0.0747

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Mannose-binding lectin deficiency Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2006- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaDec 11, 2018The 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
Benign, criteria provided, single submitterclinical testingInvitaeJan 18, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2021- -
Cystic fibrosis Other:1
risk factor, no assertion criteria providedresearchCenter for Computational Genomics and Data Science, University of AlabamaApr 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Uncertain
-0.030
Cadd
Uncertain
24
Dann
Pathogenic
1.0
DEOGEN2
Uncertain
0.62
D
Eigen
Uncertain
0.38
Eigen_PC
Benign
0.19
FATHMM_MKL
Benign
0.091
N
LIST_S2
Pathogenic
0.97
D
MetaRNN
Benign
0.0030
T
MetaSVM
Uncertain
0.062
D
MutationAssessor
Pathogenic
3.4
M
MutationTaster
Benign
0.99
A
PrimateAI
Benign
0.33
T
PROVEAN
Pathogenic
-4.9
D
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.091
MPC
0.50
ClinPred
0.067
T
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.

Other links and lift over

dbSNP: rs5030737; hg19: chr10-54531242; COSMIC: COSV64758368; API