rs11595876

Positions:

• chr10-52767002-T-C

Variant summary

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

The NM_001378373.1(MBL2):​c.*1135A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0461 in 152,020 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (226 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: MBL2 NM_001378373.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.853

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 (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBL2	NM_001378373.1	c.*1135A>G		3_prime_UTR_variant	5/5	ENST00000674931.1	NP_001365302.1
MBL2	NM_000242.3	c.*1135A>G		3_prime_UTR_variant	4/4		NP_000233.1
MBL2	NM_001378374.1	c.*1135A>G		3_prime_UTR_variant	5/5		NP_001365303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBL2	ENST00000674931	c.*1135A>G		3_prime_UTR_variant	5/5		NM_001378373.1	ENSP00000502789.1
MBL2	ENST00000373968	c.*1135A>G		3_prime_UTR_variant	4/4	1		ENSP00000363079.3
MBL2	ENST00000675947	c.*1135A>G		3_prime_UTR_variant	5/5			ENSP00000502615.1

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7019 AN: 151902 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0417

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0462

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0684

Gnomad OTH AF: 0.0445

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0461 AC: 7015 AN: 152020 Hom.: 226 Cov.: 32 AF XY: 0.0442 AC XY: 3285 AN XY: 74340

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0415

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.0462

Gnomad4 NFE AF: 0.0684

Gnomad4 OTH AF: 0.0435

Alfa AF: 0.0635 Hom.: 375

Bravo AF: 0.0447

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Mannose-binding lectin deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.25
DANN	Benign	0.45

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: rs11595876; hg19: chr10-54526762;