rs56220864

chr11-1257682-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002458.3(MUC5B):c.16422G>C(p.Glu5474Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,570,458 control chromosomes in the GnomAD database, including 840 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (64 hom., cov: 32)
  • Exomes 𝑓: 0.030 (776 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.566

Genes affected

MUC5B (HGNC:7516): (mucin 5B, oligomeric mucus/gel-forming) This gene encodes a member of the mucin family of proteins, which are highly glycosylated macromolecular components of mucus secretions. This family member is the major gel-forming mucin in mucus. It is a major contributor to the lubricating and viscoelastic properties of whole saliva, normal lung mucus and cervical mucus. This gene has been found to be up-regulated in some human diseases, including sinus mucosa of chronic rhinosinusitis (CRS), CRS with nasal polyposis, chronic obstructive pulmonary disease (COPD) and H. pylori-associated gastric disease, and it may be involved in the pathogenesis of these diseases. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026461482).
• BP6: Variant 11-1257682-G-C is Benign according to our data. Variant chr11-1257682-G-C is described in ClinVar as [Benign]. Clinvar id is 164010.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.025 (3806/152334) while in subpopulation NFE AF= 0.0327 (2227/68018). AF 95% confidence interval is 0.0316. There are 64 homozygotes in gnomad4. There are 1891 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3807 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.16422G>C	p.Glu5474Asp	missense_variant	41/49	ENST00000529681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.16422G>C	p.Glu5474Asp	missense_variant	41/49	5	NM_002458.3	P1
MUC5B	ENST00000526859.1	c.57G>C	p.Glu19Asp	missense_variant	1/6	3

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3807 AN: 152216 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.0231 AC: 4288 AN: 185316 Hom.: 67 AF XY: 0.0228 AC XY: 2310 AN XY: 101466

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.00517

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00950

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0296 AC: 41927 AN: 1418124 Hom.: 776 Cov.: 33 AF XY: 0.0289 AC XY: 20302 AN XY: 703558

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.00560

Gnomad4 ASJ exome AF: 0.0287

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00950

Gnomad4 FIN exome AF: 0.0703

Gnomad4 NFE exome AF: 0.0324

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0250 AC: 3806 AN: 152334 Hom.: 64 Cov.: 32 AF XY: 0.0254 AC XY: 1891 AN XY: 74482

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0692

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0308 Hom.: 21

Bravo AF: 0.0198

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.0156 AC: 62

ESP6500EA AF: 0.0300 AC: 247

ExAC AF: 0.0214 AC: 2526

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Glu5474Asp in exon 41 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 3.0% (247/8246) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs56220864). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	1.3
Dann	Benign	0.72
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.98	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.94	N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T
Vest4		0.012
ClinPred		0.0036	T
GERP RS		3.0
Varity_R		0.033
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56220864; hg19: chr11-1278912; COSMIC: COSV71591309; COSMIC: COSV71591309;