Genetic Variant NM_002458.3:c.6713T>C (chr11-1243593-T-C) – ACMG Classification: Benign (-20 pts)

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.6713T>C(p.Leu2238Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,589,440 control chromosomes in the GnomAD database, including 408,821 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 0.73 ( 39764 hom., cov: 23)

Exomes 𝑓: 0.71 ( 369057 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.04

Publications

20 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=1.5669541E-6).

BP6

Variant 11-1243593-T-C is Benign according to our data. Variant chr11-1243593-T-C is described in ClinVar as Benign. ClinVar VariationId is 403140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.6713T>C	p.Leu2238Pro	missense	Exon 31 of 49	NP_002449.2	Q9HC84
	MUC5B-AS1	NR_157183.1		n.57-955A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.6713T>C	p.Leu2238Pro	missense	Exon 31 of 49	ENSP00000436812.1	Q9HC84
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.57-955A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.731

AC:

107098

AN:

146430

Hom.:

39707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.747

Gnomad AMI

AF:

0.741

Gnomad AMR

AF:

0.784

Gnomad ASJ

AF:

0.686

Gnomad EAS

AF:

0.978

Gnomad SAS

AF:

0.765

Gnomad FIN

AF:

0.793

Gnomad MID

AF:

0.663

Gnomad NFE

AF:

0.682

Gnomad OTH

AF:

0.725

GnomAD2 exomes

AF:

0.750

AC:

183972

AN:

245140

AF XY:

0.745

show subpopulations

Gnomad AFR exome

AF:

0.752

Gnomad AMR exome

AF:

0.845

Gnomad ASJ exome

AF:

0.691

Gnomad EAS exome

AF:

0.983

Gnomad FIN exome

AF:

0.774

Gnomad NFE exome

AF:

0.681

Gnomad OTH exome

AF:

0.722

GnomAD4 exome

AF:

0.707

AC:

1019938

AN:

1442890

Hom.:

369057

Cov.:

126

AF XY:

0.707

AC XY:

507721

AN XY:

717958

show subpopulations

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

African (AFR)

AF:

0.742

AC:

24696

AN:

33278

American (AMR)

AF:

0.838

AC:

37385

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.684

AC:

17630

AN:

25780

East Asian (EAS)

AF:

0.978

AC:

38806

AN:

39698

South Asian (SAS)

AF:

0.763

AC:

65478

AN:

85872

European-Finnish (FIN)

AF:

0.775

AC:

40306

AN:

51988

Middle Eastern (MID)

AF:

0.683

AC:

2833

AN:

4150

European-Non Finnish (NFE)

AF:

0.683

AC:

749939

AN:

1097980

Other (OTH)

AF:

0.720

AC:

42865

AN:

59514

⚠️ 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: 0.380

Heterozygous variant carriers

15599

31198

46797

62396

77995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19126

38252

57378

76504

95630

<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:

0.732

AC:

107216

AN:

146550

Hom.:

39764

Cov.:

AF XY:

0.740

AC XY:

52755

AN XY:

71300

show subpopulations

African (AFR)

AF:

0.748

AC:

30069

AN:

40198

American (AMR)

AF:

0.785

AC:

11689

AN:

14892

Ashkenazi Jewish (ASJ)

AF:

0.686

AC:

2331

AN:

3396

East Asian (EAS)

AF:

0.978

AC:

4766

AN:

4874

South Asian (SAS)

AF:

0.764

AC:

3446

AN:

4512

European-Finnish (FIN)

AF:

0.793

AC:

7774

AN:

9804

Middle Eastern (MID)

AF:

0.652

AC:

189

AN:

290

European-Non Finnish (NFE)

AF:

0.682

AC:

44808

AN:

65658

Other (OTH)

AF:

0.729

AC:

1479

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

1152

2303

3455

4606

5758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

802

1604

2406

3208

4010

<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:

0.695

Hom.:

15969

Bravo

AF:

0.733

ESP6500AA

AF:

0.649

AC:

2768

ESP6500EA

AF:

0.564

AC:

4759

ExAC

AF:

0.737

AC:

89217

Asia WGS

AF:

0.857

AC:

2971

AN:

3466

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.48

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.015

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00031

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0000016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

-1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

0.17

REVEL

Benign

0.0030

Sift

Benign

0.15

Vest4

0.011

ClinPred

0.0059

GERP RS

-0.50

Varity_R

0.041

gMVP

0.18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over