Genetic Variant MUC5B:c.2377+25_2377+34delTGCCCTGCCC (chr11-1233859-CCCCTGCCCTG-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002458.3(MUC5B):c.2377+25_2377+34delTGCCCTGCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000765 in 1,568,244 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

MUC5B
NM_002458.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

3 publications found

Variant links:

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

MUC5B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.2377+25_2377+34delTGCCCTGCCC		intron	N/A	NP_002449.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.2377+12_2377+21delCCCTGCCCTG		intron	N/A	ENSP00000436812.1
	MUC5B	ENST00000525715.5	TSL:1	n.2435+12_2435+21delCCCTGCCCTG		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000551

AC:

AN:

181460

AF XY:

0.0000102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000130

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000706

AC:

AN:

1417230

Hom.:

AF XY:

0.00000570

AC XY:

AN XY:

701948

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000307

AC:

AN:

32584

American (AMR)

AF:

0.00

AC:

AN:

38562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25496

East Asian (EAS)

AF:

0.00

AC:

AN:

37178

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81636

European-Finnish (FIN)

AF:

0.0000206

AC:

AN:

48490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4702

European-Non Finnish (NFE)

AF:

0.00000642

AC:

AN:

1089838

Other (OTH)

AF:

0.00

AC:

AN:

58744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000356935), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.305

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151014

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73694

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41178

American (AMR)

AF:

0.00

AC:

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5052

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67596

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over