11-1243461-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002458.3(MUC5B):c.6581T>C(p.Met2194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,365,212 control chromosomes in the GnomAD database, including 339,665 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 34222 hom., cov: 18)

Exomes 𝑓: 0.61 ( 305443 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -4.89

Publications

14 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5453392E-6).

BP6

Variant 11-1243461-T-C is Benign according to our data. Variant chr11-1243461-T-C is described in ClinVar as Benign. ClinVar VariationId is 403137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.6581T>C	p.Met2194Thr	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84
MUC5B-AS1	NR_157183.1 link	n.57-823A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.6581T>C	p.Met2194Thr	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B-AS1	ENST00000532061.2 link	n.57-823A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.743

AC:

82763

AN:

111388

Hom.:

34164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.920

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.777

Gnomad ASJ

AF:

0.641

Gnomad EAS

AF:

0.967

Gnomad SAS

AF:

0.726

Gnomad FIN

AF:

0.720

Gnomad MID

AF:

0.685

Gnomad NFE

AF:

0.611

Gnomad OTH

AF:

0.711

GnomAD2 exomes

AF:

0.633

AC:

110404

AN:

174334

AF XY:

0.618

show subpopulations

Gnomad AFR exome

AF:

0.901

Gnomad AMR exome

AF:

0.805

Gnomad ASJ exome

AF:

0.573

Gnomad EAS exome

AF:

0.963

Gnomad FIN exome

AF:

0.638

Gnomad NFE exome

AF:

0.476

Gnomad OTH exome

AF:

0.617

GnomAD4 exome

AF:

0.615

AC:

770793

AN:

1253722

Hom.:

305443

Cov.:

AF XY:

0.618

AC XY:

384414

AN XY:

622490

show subpopulations

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

African (AFR)

AF:

0.918

AC:

28855

AN:

31426

American (AMR)

AF:

0.835

AC:

30857

AN:

36946

Ashkenazi Jewish (ASJ)

AF:

0.632

AC:

14180

AN:

22426

East Asian (EAS)

AF:

0.985

AC:

33930

AN:

34462

South Asian (SAS)

AF:

0.738

AC:

55536

AN:

75244

European-Finnish (FIN)

AF:

0.701

AC:

31583

AN:

45080

Middle Eastern (MID)

AF:

0.651

AC:

2513

AN:

3858

European-Non Finnish (NFE)

AF:

0.566

AC:

538859

AN:

952540

Other (OTH)

AF:

0.666

AC:

34480

AN:

51740

⚠️ 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: 0.366

Heterozygous variant carriers

9763

19526

29288

39051

48814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12866

25732

38598

51464

64330

<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:

0.743

AC:

82871

AN:

111490

Hom.:

34222

Cov.:

AF XY:

0.750

AC XY:

40414

AN XY:

53904

show subpopulations

African (AFR)

AF:

0.920

AC:

31274

AN:

33980

American (AMR)

AF:

0.778

AC:

8623

AN:

11088

Ashkenazi Jewish (ASJ)

AF:

0.641

AC:

1635

AN:

2550

East Asian (EAS)

AF:

0.966

AC:

2590

AN:

2680

South Asian (SAS)

AF:

0.725

AC:

2428

AN:

3350

European-Finnish (FIN)

AF:

0.720

AC:

5192

AN:

7212

Middle Eastern (MID)

AF:

0.679

AC:

152

AN:

224

European-Non Finnish (NFE)

AF:

0.610

AC:

29503

AN:

48330

Other (OTH)

AF:

0.716

AC:

1035

AN:

1446

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

568

1136

1705

2273

2841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.525

Hom.:

3027

ESP6500AA

AF:

0.842

AC:

3120

ESP6500EA

AF:

0.488

AC:

3886

ExAC

AF:

0.569

AC:

57470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.0040

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.014

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.00024

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0000015

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.34

PhyloP100

-4.9

PrimateAI

Benign

0.21

PROVEAN

Benign

0.92

REVEL

Benign

0.030

Sift

Benign

0.81

Vest4

0.021

ClinPred

0.0021

GERP RS

-4.5

Varity_R

0.038

gMVP

0.19

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over