rs56232219

Variant names:

• chr11-1254758-T-C
• rs56232219
• NM_002458.3:c.15542T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.15542T>C​(p.Leu5181Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,612,898 control chromosomes in the GnomAD database, including 904 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (62 hom., cov: 33)
  • Exomes 𝑓: 0.030 (842 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.187
• Publications: 8 publications found

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]

MUC5B Gene-Disease associations (from GenCC):

• interstitial lung disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035450459).
• BP6: Variant 11-1254758-T-C is Benign according to our data. Variant chr11-1254758-T-C is described in ClinVar as Benign. ClinVar VariationId is 164004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.025 (3804/152332) while in subpopulation NFE AF = 0.0327 (2225/68016). AF 95% confidence interval is 0.0316. There are 62 homozygotes in GnomAd4. There are 1893 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.15542T>C	p.Leu5181Pro	missense_variant	Exon 35 of 49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.15542T>C	p.Leu5181Pro	missense_variant	Exon 35 of 49	5	NM_002458.3	ENSP00000436812.1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3805 AN: 152214 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0286

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0691

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0267 AC: 6609 AN: 247776 AF XY: 0.0265

Gnomad AFR exome AF: 0.0152

Gnomad AMR exome AF: 0.00513

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0744

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0301 AC: 44002 AN: 1460566 Hom.: 842 Cov.: 34 AF XY: 0.0295 AC XY: 21409 AN XY: 726550

African (AFR) AF: 0.0119 AC: 397 AN: 33480

American (AMR) AF: 0.00564 AC: 252 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 761 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00951 AC: 820 AN: 86252

European-Finnish (FIN) AF: 0.0726 AC: 3808 AN: 52446

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5764

European-Non Finnish (NFE) AF: 0.0326 AC: 36277 AN: 1111746

Other (OTH) AF: 0.0275 AC: 1660 AN: 60354

GnomAD4 genome AF: 0.0250 AC: 3804 AN: 152332 Hom.: 62 Cov.: 33 AF XY: 0.0254 AC XY: 1893 AN XY: 74498

African (AFR) AF: 0.0131 AC: 544 AN: 41584

American (AMR) AF: 0.00745 AC: 114 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 99 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4830

European-Finnish (FIN) AF: 0.0691 AC: 734 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0327 AC: 2225 AN: 68016

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0286 Hom.: 200

Bravo AF: 0.0198

TwinsUK AF: 0.0302 AC: 112

ESP6500AA AF: 0.0153 AC: 66

ESP6500EA AF: 0.0321 AC: 273

ExAC AF: 0.0278 AC: 3357

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0263

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu5181Pro in exon 35 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 3.2% (273/8496) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs56232219).

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.41
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		-0.19
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.57	N
Sift	Benign	0.29	T
Vest4		0.18
ClinPred		0.00015	T
GERP RS		-0.018
Varity_R		0.066
gMVP		0.82
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56232219; hg19: chr11-1275988;