chr11-1244706-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002458.3(MUC5B):c.7826T>C(p.Leu2609Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,602,980 control chromosomes in the GnomAD database, including 690 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2609L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 46 hom., cov: 31)

Exomes 𝑓: 0.024 ( 644 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.28

Publications

7 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=0.0044881403).

BP6

Variant 11-1244706-T-C is Benign according to our data. Variant chr11-1244706-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 403181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0231 (3447/149404) while in subpopulation NFE AF = 0.0283 (1910/67434). AF 95% confidence interval is 0.0273. There are 46 homozygotes in GnomAd4. There are 1696 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.7826T>C	p.Leu2609Pro	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1 link	n.57-2068A>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.7826T>C	p.Leu2609Pro	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2 link	n.57-2068A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.0231

AC:

3446

AN:

149274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0232

Gnomad ASJ

AF:

0.0120

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0346

Gnomad MID

AF:

0.0483

Gnomad NFE

AF:

0.0283

Gnomad OTH

AF:

0.0233

GnomAD2 exomes

AF:

0.0134

AC:

3275

AN:

245272

AF XY:

0.0131

show subpopulations

Gnomad AFR exome

AF:

0.0103

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.00937

Gnomad EAS exome

AF:

0.00375

Gnomad FIN exome

AF:

0.0228

Gnomad NFE exome

AF:

0.0169

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.0236

AC:

34309

AN:

1453576

Hom.:

644

Cov.:

147

AF XY:

0.0232

AC XY:

16768

AN XY:

723102

show subpopulations

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

African (AFR)

AF:

0.0139

AC:

465

AN:

33336

American (AMR)

AF:

0.0136

AC:

606

AN:

44482

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

390

AN:

26052

East Asian (EAS)

AF:

0.00517

AC:

205

AN:

39614

South Asian (SAS)

AF:

0.00893

AC:

768

AN:

86050

European-Finnish (FIN)

AF:

0.0288

AC:

1529

AN:

53154

Middle Eastern (MID)

AF:

0.0268

AC:

152

AN:

5674

European-Non Finnish (NFE)

AF:

0.0260

AC:

28763

AN:

1105150

Other (OTH)

AF:

0.0238

AC:

1431

AN:

60064

⚠️ 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: 0.332

Heterozygous variant carriers

2149

4298

6446

8595

10744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1024

2048

3072

4096

5120

<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:

0.0231

AC:

3447

AN:

149404

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1696

AN XY:

72992

show subpopulations

African (AFR)

AF:

0.0160

AC:

642

AN:

40170

American (AMR)

AF:

0.0232

AC:

349

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

AN:

3428

East Asian (EAS)

AF:

0.00502

AC:

AN:

4982

South Asian (SAS)

AF:

0.0116

AC:

AN:

4656

European-Finnish (FIN)

AF:

0.0346

AC:

361

AN:

10424

Middle Eastern (MID)

AF:

0.0515

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0283

AC:

1910

AN:

67434

Other (OTH)

AF:

0.0231

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

149

298

448

597

746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0207

Hom.:

Bravo

AF:

0.0218

ESP6500AA

AF:

0.00407

AC:

ESP6500EA

AF:

0.0104

AC:

ExAC

AF:

0.0204

AC:

2470

ClinVar

Significance: Likely 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:Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.49

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.015

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-3.3

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.69

REVEL

Benign

0.0050

Sift

Benign

0.099

Vest4

0.034

ClinPred

0.00048

GERP RS

-1.6

Varity_R

0.070

gMVP

0.15

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