Genetic Variant MUC5B:p.Arg2200Arg (chr11-1243480-A-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_002458.3(MUC5B):c.6600A>T(p.Arg2200Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000744 in 1,343,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R2200R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 19)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MUC5B
NM_002458.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.20

Publications

6 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 links:

MUC5B-AS1 (HGNC:53936): (MUC5B antisense RNA 1)

MUC5B-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP7

Synonymous conserved (PhyloP=-2.2 with no splicing effect.

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.6600A>T	p.Arg2200Arg	synonymous	Exon 31 of 49	NP_002449.2
	MUC5B-AS1	NR_157183.1		n.57-842T>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.6600A>T	p.Arg2200Arg	synonymous	Exon 31 of 49	ENSP00000436812.1
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.57-842T>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

105052

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

AC:

AN:

185632

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.44e-7

AC:

AN:

1343964

Hom.:

Cov.:

104

AF XY:

0.00000149

AC XY:

AN XY:

669558

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31762

American (AMR)

AF:

0.00

AC:

AN:

41664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24758

East Asian (EAS)

AF:

0.00

AC:

AN:

36928

South Asian (SAS)

AF:

0.00

AC:

AN:

82014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

9.83e-7

AC:

AN:

1017672

Other (OTH)

AF:

0.00

AC:

AN:

55942

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

105052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50796

African (AFR)

AF:

0.00

AC:

AN:

30914

American (AMR)

AF:

0.00

AC:

AN:

10428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2474

East Asian (EAS)

AF:

0.00

AC:

AN:

2098

South Asian (SAS)

AF:

0.00

AC:

AN:

3244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

46832

Other (OTH)

AF:

0.00

AC:

AN:

1386

Alfa

AF:

0.0000400

Hom.:

1107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

2.2

(source)

DANN

Benign

0.73

PhyloP100

-2.2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over