NM_002458.3:c.2007T>C

Variant names:

• chr11-1232712-T-C
• rs908229
• NM_002458.3:c.2007T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002458.3(MUC5B):​c.2007T>C​(p.Tyr669Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,597,398 control chromosomes in the GnomAD database, including 213,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20978 hom., cov: 35)
  • Exomes 𝑓: 0.51 (192122 hom.)
• Consequence: MUC5B NM_002458.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.577
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• interstitial lung disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-1232712-T-C is Benign according to our data. Variant chr11-1232712-T-C is described in ClinVar as Benign. ClinVar VariationId is 163997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.2007T>C	p.Tyr669Tyr	synonymous_variant	Exon 17 of 49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.2007T>C	p.Tyr669Tyr	synonymous_variant	Exon 17 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B	ENST00000525715.5	n.2065T>C		non_coding_transcript_exon_variant	Exon 17 of 26	1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79434 AN: 152014 Hom.: 20955 Cov.: 35

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.533

GnomAD2 exomes AF: 0.628 AC: 141750 AN: 225866 AF XY: 0.626

Gnomad AFR exome AF: 0.572

Gnomad AMR exome AF: 0.673

Gnomad ASJ exome AF: 0.640

Gnomad EAS exome AF: 0.697

Gnomad FIN exome AF: 0.665

Gnomad NFE exome AF: 0.607

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.514 AC: 742835 AN: 1445266 Hom.: 192122 Cov.: 69 AF XY: 0.513 AC XY: 367971 AN XY: 717384

African (AFR) AF: 0.492 AC: 16327 AN: 33214

American (AMR) AF: 0.614 AC: 26121 AN: 42560

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 13936 AN: 25808

East Asian (EAS) AF: 0.701 AC: 27310 AN: 38940

South Asian (SAS) AF: 0.505 AC: 42378 AN: 83912

European-Finnish (FIN) AF: 0.576 AC: 29136 AN: 50626

Middle Eastern (MID) AF: 0.520 AC: 2989 AN: 5752

European-Non Finnish (NFE) AF: 0.501 AC: 553813 AN: 1104702

Other (OTH) AF: 0.516 AC: 30825 AN: 59752

GnomAD4 genome AF: 0.523 AC: 79503 AN: 152132 Hom.: 20978 Cov.: 35 AF XY: 0.529 AC XY: 39318 AN XY: 74374

African (AFR) AF: 0.495 AC: 20547 AN: 41512

American (AMR) AF: 0.589 AC: 8999 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1899 AN: 3472

East Asian (EAS) AF: 0.662 AC: 3418 AN: 5164

South Asian (SAS) AF: 0.506 AC: 2444 AN: 4826

European-Finnish (FIN) AF: 0.588 AC: 6220 AN: 10580

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.503 AC: 34203 AN: 67980

Other (OTH) AF: 0.536 AC: 1133 AN: 2114

Alfa AF: 0.556 Hom.: 3710

Bravo AF: 0.523

Asia WGS AF: 0.613 AC: 2130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tyr669Tyr in exon 17 of MUC5B: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 40.0% (1720/4300) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs908229). -

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
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.43
DANN	Benign	0.18
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs908229; hg19: chr11-1253942; COSMIC: COSV71590016; COSMIC: COSV71590016;