11-1243401-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002458.3(MUC5B):c.6521A>G(p.Asn2174Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,234,076 control chromosomes in the GnomAD database, including 73,240 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 0.23 ( 3585 hom., cov: 22)

Exomes 𝑓: 0.22 ( 69655 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.04

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013912916).

BP6

Variant 11-1243401-A-G is Benign according to our data. Variant chr11-1243401-A-G is described in ClinVar as Benign. ClinVar VariationId is 403136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3585 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.6521A>G	p.Asn2174Ser	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1 link	n.57-763T>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.6521A>G	p.Asn2174Ser	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2 link	n.57-763T>C		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

28094

AN:

122558

Hom.:

3575

Cov.:

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.247

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.509

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.213

Gnomad MID

AF:

0.229

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.250

GnomAD2 exomes

AF:

0.282

AC:

40851

AN:

144808

AF XY:

0.276

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.246

Gnomad EAS exome

AF:

0.617

Gnomad FIN exome

AF:

0.246

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.283

GnomAD4 exome

AF:

0.222

AC:

247084

AN:

1111424

Hom.:

69655

Cov.:

118

AF XY:

0.224

AC XY:

123993

AN XY:

554098

show subpopulations

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

African (AFR)

AF:

0.145

AC:

3882

AN:

26844

American (AMR)

AF:

0.252

AC:

7725

AN:

30714

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

5031

AN:

21498

East Asian (EAS)

AF:

0.600

AC:

20421

AN:

34030

South Asian (SAS)

AF:

0.225

AC:

15940

AN:

70746

European-Finnish (FIN)

AF:

0.256

AC:

11528

AN:

44998

Middle Eastern (MID)

AF:

0.199

AC:

866

AN:

4348

European-Non Finnish (NFE)

AF:

0.205

AC:

169907

AN:

830076

Other (OTH)

AF:

0.245

AC:

11784

AN:

48170

⚠️ 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: 0.316

Heterozygous variant carriers

9980

19960

29941

39921

49901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2924

5848

8772

11696

14620

<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:

0.229

AC:

28124

AN:

122652

Hom.:

3585

Cov.:

AF XY:

0.225

AC XY:

13339

AN XY:

59166

show subpopulations

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

African (AFR)

AF:

0.165

AC:

5749

AN:

34790

American (AMR)

AF:

0.248

AC:

3008

AN:

12118

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

683

AN:

2852

East Asian (EAS)

AF:

0.509

AC:

1804

AN:

3544

South Asian (SAS)

AF:

0.206

AC:

780

AN:

3786

European-Finnish (FIN)

AF:

0.213

AC:

1717

AN:

8060

Middle Eastern (MID)

AF:

0.220

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.250

AC:

13703

AN:

54852

Other (OTH)

AF:

0.258

AC:

432

AN:

1674

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.321

Heterozygous variant carriers

1244

2488

3731

4975

6219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.289

Hom.:

1306

ExAC

AF:

0.130

AC:

13131

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.050

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.21

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.015

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0014

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.55

PhyloP100

-1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

0.49

REVEL

Benign

0.024

Sift

Benign

0.76

Vest4

0.024

ClinPred

0.000019

GERP RS

0.21

Varity_R

0.019

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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