11-1245466-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_002458.3(MUC5B):c.8586A>C(p.Pro2862Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,095,550 control chromosomes in the GnomAD database, including 77,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 2950 hom., cov: 17)

Exomes 𝑓: 0.18 ( 77194 hom. )

Failed GnomAD Quality Control

Consequence

MUC5B
NM_002458.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.58

Publications

4 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.06).

BP6

Variant 11-1245466-A-C is Benign according to our data. Variant chr11-1245466-A-C is described in ClinVar as Benign. ClinVar VariationId is 403147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.58 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 77194 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.8586A>C	p.Pro2862Pro	synonymous_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84
MUC5B-AS1	NR_157183.1 link	n.57-2828T>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.8586A>C	p.Pro2862Pro	synonymous_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B-AS1	ENST00000532061.2 link	n.57-2828T>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

14723

AN:

73454

Hom.:

2947

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.225

Gnomad ASJ

AF:

0.238

Gnomad EAS

AF:

0.459

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.236

GnomAD2 exomes

AF:

0.266

AC:

44800

AN:

168454

AF XY:

0.260

show subpopulations

Gnomad AFR exome

AF:

0.235

Gnomad AMR exome

AF:

0.361

Gnomad ASJ exome

AF:

0.270

Gnomad EAS exome

AF:

0.575

Gnomad FIN exome

AF:

0.154

Gnomad NFE exome

AF:

0.215

Gnomad OTH exome

AF:

0.289

GnomAD4 exome

AF:

0.178

AC:

194919

AN:

1095550

Hom.:

77194

Cov.:

AF XY:

0.184

AC XY:

100334

AN XY:

543980

show subpopulations

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

African (AFR)

AF:

0.192

AC:

4891

AN:

25488

American (AMR)

AF:

0.298

AC:

8929

AN:

29926

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

5575

AN:

18950

East Asian (EAS)

AF:

0.647

AC:

19717

AN:

30480

South Asian (SAS)

AF:

0.258

AC:

15841

AN:

61354

European-Finnish (FIN)

AF:

0.326

AC:

11847

AN:

36324

Middle Eastern (MID)

AF:

0.258

AC:

786

AN:

3048

European-Non Finnish (NFE)

AF:

0.138

AC:

116595

AN:

844784

Other (OTH)

AF:

0.238

AC:

10738

AN:

45196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

6729

13457

20186

26914

33643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1056

2112

3168

4224

5280

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.200

AC:

14737

AN:

73506

Hom.:

2950

Cov.:

AF XY:

0.193

AC XY:

6796

AN XY:

35228

show subpopulations

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

African (AFR)

AF:

0.175

AC:

3618

AN:

20650

American (AMR)

AF:

0.226

AC:

1498

AN:

6632

Ashkenazi Jewish (ASJ)

AF:

0.238

AC:

377

AN:

1586

East Asian (EAS)

AF:

0.458

AC:

1055

AN:

2306

South Asian (SAS)

AF:

0.224

AC:

531

AN:

2374

European-Finnish (FIN)

AF:

0.166

AC:

730

AN:

4394

Middle Eastern (MID)

AF:

0.253

AC:

AN:

162

European-Non Finnish (NFE)

AF:

0.193

AC:

6574

AN:

34006

Other (OTH)

AF:

0.242

AC:

250

AN:

1034

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.274

Heterozygous variant carriers

896

1792

2688

3584

4480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<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:

0.389

Hom.:

2638

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

- -

Nov 12, 2018

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

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.1

(source)

DANN

Benign

0.60

PhyloP100

-3.6

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