11-1246473-G-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.9593G>C(p.Ser3198Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,608,120 control chromosomes in the GnomAD database, including 966 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 0.025 ( 72 hom., cov: 32)

Exomes 𝑓: 0.028 ( 894 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.12

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037986338).

BP6

Variant 11-1246473-G-C is Benign according to our data. Variant chr11-1246473-G-C is described in ClinVar as Benign. ClinVar VariationId is 403154.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 = 0.0251 (3794/151156) while in subpopulation NFE AF = 0.0327 (2216/67694). AF 95% confidence interval is 0.0316. There are 72 homozygotes in GnomAd4. There are 1886 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 72 AR gene

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.9593G>C	p.Ser3198Thr	missense	Exon 31 of 49	NP_002449.2	Q9HC84
	MUC5B-AS1	NR_157183.1		n.56+3148C>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.9593G>C	p.Ser3198Thr	missense	Exon 31 of 49	ENSP00000436812.1	Q9HC84
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.56+3148C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3795

AN:

151032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00762

Gnomad ASJ

AF:

0.0296

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00820

Gnomad FIN

AF:

0.0696

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0327

Gnomad OTH

AF:

0.0221

GnomAD2 exomes

AF:

0.0246

AC:

6092

AN:

247928

AF XY:

0.0245

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.00487

Gnomad ASJ exome

AF:

0.0269

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0703

Gnomad NFE exome

AF:

0.0314

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0278

AC:

40546

AN:

1456964

Hom.:

894

Cov.:

127

AF XY:

0.0273

AC XY:

19810

AN XY:

724928

show subpopulations

African (AFR)

AF:

0.0113

AC:

378

AN:

33448

American (AMR)

AF:

0.00539

AC:

241

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

736

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00916

AC:

790

AN:

86200

European-Finnish (FIN)

AF:

0.0712

AC:

3790

AN:

53230

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0298

AC:

33024

AN:

1107598

Other (OTH)

AF:

0.0259

AC:

1560

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

2672

5344

8016

10688

13360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1172

2344

3516

4688

5860

<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:

0.0251

AC:

3794

AN:

151156

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

1886

AN XY:

73852

show subpopulations

African (AFR)

AF:

0.0131

AC:

539

AN:

41126

American (AMR)

AF:

0.00761

AC:

116

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.0296

AC:

102

AN:

3448

East Asian (EAS)

AF:

0.000198

AC:

AN:

5056

South Asian (SAS)

AF:

0.00821

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.0696

AC:

734

AN:

10542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0327

AC:

2216

AN:

67694

Other (OTH)

AF:

0.0218

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

184

368

553

737

921

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:

0.0270

Hom.:

Bravo

AF:

0.0199

ESP6500AA

AF:

0.0144

AC:

ESP6500EA

AF:

0.0277

AC:

236

ExAC

AF:

0.0238

AC:

2885

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.019

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.029

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

PhyloP100

-3.1

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.060

REVEL

Benign

0.0030

Sift

Benign

1.0

Vest4

0.020

ClinPred

0.00050

GERP RS

-4.6

Varity_R

0.034

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