rs5030737

chr10-52771482-G-Achr10-52771482-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:2 O:1
• Conservation: PhyloP100: 0.972

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]

ACMG classification

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
MBL2	NM_001378373.1	c.154C>T	p.Arg52Cys	missense_variant	2/5	ENST00000674931.1
MBL2	NM_000242.3	c.154C>T	p.Arg52Cys	missense_variant	1/4
MBL2	NM_001378374.1	c.154C>T	p.Arg52Cys	missense_variant	2/5

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7514 AN: 152044 Hom.: 282 Cov.: 32

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

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

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

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:2 Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mannose-binding lectin deficiency Pathogenic:2 Benign:1

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. -
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	- -

not provided Uncertain:1 Benign: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	Invitae	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	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

Other links and lift over

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