rs56392418

chr1-11046591-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006610.4(MASP2):c.377C>T(p.Pro126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0065 in 1,613,836 control chromosomes in the GnomAD database, including 580 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (297 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (283 hom.)
• Consequence: MASP2 NM_006610.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.687

Genes affected

MASP2 (HGNC:6902): (MBL associated serine protease 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is proteolytically processed to generate A and B chains that heterodimerize to form the mature protease. This protease cleaves complement components C2 and C4 in order to generate C3 convertase in the lectin pathway of the complement system. The encoded protease also plays a role in the coagulation cascade through cleavage of prothrombin to form thrombin. Myocardial infarction and acute stroke patients exhibit reduced serum concentrations of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014110506).
• BP6: Variant 1-11046591-G-A is Benign according to our data. Variant chr1-11046591-G-A is described in ClinVar as [Benign]. Clinvar id is 291807.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MASP2	NM_006610.4	c.377C>T	p.Pro126Leu	missense_variant	3/11	ENST00000400897.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MASP2	ENST00000400897.8	c.377C>T	p.Pro126Leu	missense_variant	3/11	1	NM_006610.4	P1

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5197 AN: 152212 Hom.: 296 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.00911 AC: 2284 AN: 250762 Hom.: 109 AF XY: 0.00633 AC XY: 860 AN XY: 135764

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.00593

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00362 AC: 5286 AN: 1461506 Hom.: 283 Cov.: 32 AF XY: 0.00304 AC XY: 2209 AN XY: 727036

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.00793

GnomAD4 genome AF: 0.0342 AC: 5209 AN: 152330 Hom.: 297 Cov.: 33 AF XY: 0.0328 AC XY: 2440 AN XY: 74498

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0176 Hom.: 84

Bravo AF: 0.0393

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.115 AC: 505

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0111 AC: 1351

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency due to MASP-2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.071	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N;D
REVEL	Benign	0.034
Sift	Benign	0.030	D;D
Sift4G	Benign	0.085	T;T
Polyphen		0.54	P;B
Vest4		0.098
MPC		0.063
ClinPred		0.0086	T
GERP RS		2.8
Varity_R		0.078
gMVP		0.55

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: rs56392418; hg19: chr1-11106648; COSMIC: COSV68896941; COSMIC: COSV68896941;