rs1800450

chr10-52771475-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001378373.1(MBL2):c.161G>A(p.Gly54Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,613,658 control chromosomes in the GnomAD database, including 16,347 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 0.12 (1251 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15096 hom.)
• Consequence: MBL2 NM_001378373.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3 O:1
• Conservation: PhyloP100: 2.56

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017509758).
• BP6: Variant 10-52771475-C-T is Benign according to our data. Variant chr10-52771475-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14350.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, not_provided=1, Likely_benign=1}. Variant chr10-52771475-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBL2	NM_001378373.1	c.161G>A	p.Gly54Asp	missense_variant	2/5	ENST00000674931.1
MBL2	NM_000242.3	c.161G>A	p.Gly54Asp	missense_variant	1/4
MBL2	NM_001378374.1	c.161G>A	p.Gly54Asp	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBL2	ENST00000674931.1	c.161G>A	p.Gly54Asp	missense_variant	2/5		NM_001378373.1	P1
MBL2	ENST00000373968.3	c.161G>A	p.Gly54Asp	missense_variant	1/4	1		P1
MBL2	ENST00000675947.1	c.161G>A	p.Gly54Asp	missense_variant	2/5			P1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17710 AN: 152062 Hom.: 1247 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.141 AC: 35332 AN: 251074 Hom.: 2772 AF XY: 0.140 AC XY: 19047 AN XY: 135682

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.141 AC: 206058 AN: 1461474 Hom.: 15096 Cov.: 32 AF XY: 0.141 AC XY: 102571 AN XY: 727062

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.188

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.116 AC: 17719 AN: 152184 Hom.: 1251 Cov.: 32 AF XY: 0.119 AC XY: 8860 AN XY: 74396

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.124

Alfa AF: 0.138 Hom.: 3435

Bravo AF: 0.116

TwinsUK AF: 0.154 AC: 570

ALSPAC AF: 0.151 AC: 583

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.140 AC: 1208

ExAC AF: 0.139 AC: 16859

Asia WGS AF: 0.142 AC: 495 AN: 3478

EpiCase AF: 0.139

EpiControl AF: 0.142

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mannose-binding lectin deficiency Pathogenic:1 Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 05, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MBL2: PS3:Moderate, PS4:Supporting -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.052, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.69	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	0.00010	P
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.18
MPC		0.50
ClinPred		0.068	T
GERP RS		4.0
Varity_R		0.87
gMVP		0.82

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: rs1800450; hg19: chr10-54531235; COSMIC: COSV64758159;