rs7116614

Variant names:

• chr11-1234543-C-A
• rs7116614
• NM_002458.3:c.2493C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-1234543-C-A
• chr11-1234543-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_002458.3(MUC5B):​c.2493C>A​(p.Cys831*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C831C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MUC5B NM_002458.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.659
• Publications: 15 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.2493C>A	p.Cys831*	stop_gained	Exon 21 of 49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.2493C>A	p.Cys831*	stop_gained	Exon 21 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B	ENST00000525715.5	n.2551C>A		non_coding_transcript_exon_variant	Exon 21 of 26	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428048 Hom.: 0 Cov.: 49 AF XY: 0.00 AC XY: 0 AN XY: 707020

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

African (AFR) AF: 0.00 AC: 0 AN: 32810

American (AMR) AF: 0.0000248 AC: 1 AN: 40260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25446

East Asian (EAS) AF: 0.00 AC: 0 AN: 37670

South Asian (SAS) AF: 0.00 AC: 0 AN: 81268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095834

Other (OTH) AF: 0.00 AC: 0 AN: 59142

⚠️ 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.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.22	N
PhyloP100		-0.66
Vest4		0.87
GERP RS		-8.2
Mutation Taster		=51/149	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs7116614; hg19: chr11-1255773;