Genetic Variant MUC5B:p.Ala2061Gly (chr11-1243062-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002458.3(MUC5B):c.6182C>G(p.Ala2061Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00912 in 1,611,596 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2061V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0074 ( 13 hom., cov: 30)

Exomes 𝑓: 0.0093 ( 303 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

12 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003387034).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00741 (1123/151462) while in subpopulation SAS AF = 0.0282 (135/4788). AF 95% confidence interval is 0.0243. There are 13 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.6182C>G	p.Ala2061Gly	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84
MUC5B-AS1	NR_157183.1 link	n.57-424G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.6182C>G	p.Ala2061Gly	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B-AS1	ENST00000532061.2 link	n.57-424G>C		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.00747

AC:

1131

AN:

151344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00173

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00980

Gnomad ASJ

AF:

0.0383

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.000666

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.00838

Gnomad OTH

AF:

0.0149

GnomAD2 exomes

AF:

0.0118

AC:

2922

AN:

248354

AF XY:

0.0137

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00706

Gnomad ASJ exome

AF:

0.0452

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.000655

Gnomad NFE exome

AF:

0.00903

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.00930

AC:

13577

AN:

1460134

Hom.:

303

Cov.:

134

AF XY:

0.0104

AC XY:

7521

AN XY:

726390

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

33462

American (AMR)

AF:

0.00745

AC:

333

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

1113

AN:

26096

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0357

AC:

3077

AN:

86228

European-Finnish (FIN)

AF:

0.000694

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.0494

AC:

276

AN:

5586

European-Non Finnish (NFE)

AF:

0.00710

AC:

7892

AN:

1110790

Other (OTH)

AF:

0.0130

AC:

781

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1143

2286

3430

4573

5716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.00741

AC:

1123

AN:

151462

Hom.:

Cov.:

AF XY:

0.00775

AC XY:

574

AN XY:

74018

show subpopulations

African (AFR)

AF:

0.00172

AC:

AN:

41262

American (AMR)

AF:

0.00978

AC:

149

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.0383

AC:

133

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5134

South Asian (SAS)

AF:

0.0282

AC:

135

AN:

4788

European-Finnish (FIN)

AF:

0.000666

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00838

AC:

568

AN:

67756

Other (OTH)

AF:

0.0142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00998

Hom.:

ExAC

AF:

0.0119

AC:

1437

EpiCase

AF:

0.0147

EpiControl

AF:

0.0133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.59

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.023

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

PhyloP100

-1.1

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.93

REVEL

Benign

0.030

Sift

Benign

0.063

Vest4

0.038

ClinPred

0.0046

GERP RS

-2.0

Varity_R

0.047

gMVP

0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over