11-1244709-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_002458.3(MUC5B):c.7829C>G(p.Thr2610Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 1,610,006 control chromosomes in the GnomAD database, including 1 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 0.019 ( 0 hom., cov: 31)

Exomes 𝑓: 0.029 ( 1 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.172

Publications

5 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 -10 ACMG points.

PM2

Variant has high frequency in the NFE (0.0313) population. However there is too low homozygotes in high coverage region: (expected more than 317, got 1).

BP4

Computational evidence support a benign effect (MetaRNN=0.00386253).

BP6

Variant 11-1244709-C-G is Benign according to our data. Variant chr11-1244709-C-G is described in ClinVar as Benign. ClinVar VariationId is 403144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.7829C>G	p.Thr2610Ser	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84
MUC5B-AS1	NR_157183.1 link	n.57-2071G>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.7829C>G	p.Thr2610Ser	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B-AS1	ENST00000532061.2 link	n.57-2071G>C		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2831

AN:

150770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00539

Gnomad ASJ

AF:

0.0215

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00562

Gnomad FIN

AF:

0.0492

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0160

GnomAD2 exomes

AF:

0.0229

AC:

5665

AN:

247676

AF XY:

0.0228

show subpopulations

Gnomad AFR exome

AF:

0.0133

Gnomad AMR exome

AF:

0.00349

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0697

Gnomad NFE exome

AF:

0.0290

Gnomad OTH exome

AF:

0.0211

GnomAD4 exome

AF:

0.0290

AC:

42363

AN:

1459118

Hom.:

Cov.:

151

AF XY:

0.0284

AC XY:

20612

AN XY:

725838

show subpopulations

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

African (AFR)

AF:

0.0116

AC:

389

AN:

33428

American (AMR)

AF:

0.00553

AC:

247

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

730

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00882

AC:

760

AN:

86138

European-Finnish (FIN)

AF:

0.0673

AC:

3573

AN:

53062

Middle Eastern (MID)

AF:

0.00452

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0316

AC:

35053

AN:

1110054

Other (OTH)

AF:

0.0263

AC:

1585

AN:

60252

⚠️ 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: 0.343

Heterozygous variant carriers

3691

7382

11073

14764

18455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

1326

2652

3978

5304

6630

<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:

0.0188

AC:

2830

AN:

150888

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1422

AN XY:

73782

show subpopulations

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

African (AFR)

AF:

0.0112

AC:

462

AN:

41350

American (AMR)

AF:

0.00538

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

AN:

3434

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00542

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.0492

AC:

508

AN:

10334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0244

AC:

1644

AN:

67278

Other (OTH)

AF:

0.0158

AC:

AN:

2086

⚠️ 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: 0.351

Heterozygous variant carriers

122

244

366

488

610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

102

136

170

<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:

0.0151

Hom.:

ESP6500AA

AF:

0.0160

AC:

ESP6500EA

AF:

0.0325

AC:

273

ExAC

AF:

0.0273

AC:

3302

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.0

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.025

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.17

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.72

REVEL

Benign

0.014

Sift

Pathogenic

0.0

Vest4

0.050

ClinPred

0.011

GERP RS

0.40

Varity_R

0.10

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(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