11-1225746-C-T

Variant names:

• chr11-1225746-C-T
• rs56037586
• NM_002458.3:c.127+9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.127+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,603,308 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (20 hom.)
• Consequence: MUC5B NM_002458.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0940
• Publications: 0 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=-0.83).
• BP6: Variant 11-1225746-C-T is Benign according to our data. Variant chr11-1225746-C-T is described in ClinVar as [Benign]. Clinvar id is 778507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0094 (1430/152200) while in subpopulation AFR AF = 0.0321 (1331/41516). AF 95% confidence interval is 0.0306. There are 18 homozygotes in GnomAd4. There are 661 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.127+9C>T		intron_variant	Intron 2 of 48	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.127+9C>T		intron_variant	Intron 2 of 48	5	NM_002458.3	ENSP00000436812.1
MUC5B	ENST00000525715.5	n.185+9C>T		intron_variant	Intron 2 of 25	1

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 1425 AN: 152080 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0320

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00202 AC: 461 AN: 228720 AF XY: 0.00171

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.000827

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000388

Gnomad OTH exome AF: 0.00141

GnomAD4 exome AF: 0.000931 AC: 1351 AN: 1451108 Hom.: 20 Cov.: 33 AF XY: 0.000825 AC XY: 595 AN XY: 720778

African (AFR) AF: 0.0335 AC: 1117 AN: 33296

American (AMR) AF: 0.00124 AC: 54 AN: 43390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39284

South Asian (SAS) AF: 0.000142 AC: 12 AN: 84308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51674

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5746

European-Non Finnish (NFE) AF: 0.0000217 AC: 24 AN: 1107510

Other (OTH) AF: 0.00230 AC: 138 AN: 59966

GnomAD4 genome AF: 0.00940 AC: 1430 AN: 152200 Hom.: 18 Cov.: 33 AF XY: 0.00888 AC XY: 661 AN XY: 74398

African (AFR) AF: 0.0321 AC: 1331 AN: 41516

American (AMR) AF: 0.00497 AC: 76 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00637 Hom.: 14

Bravo AF: 0.0106

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.50
PhyloP100		0.094
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56037586; hg19: chr11-1246976;