rs145066684

Variant names:

• chr11-1251598-T-C
• rs145066684
• NM_002458.3:c.14718T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002458.3(MUC5B):​c.14718T>C​(p.Pro4906Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 1,612,970 control chromosomes in the GnomAD database, including 782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (50 hom., cov: 33)
  • Exomes 𝑓: 0.028 (732 hom.)
• Consequence: MUC5B NM_002458.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -7.85
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 11-1251598-T-C is Benign according to our data. Variant chr11-1251598-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 403198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3224/152332) while in subpopulation NFE AF = 0.0299 (2033/68018). AF 95% confidence interval is 0.0288. There are 50 homozygotes in GnomAd4. There are 1626 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 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.14718T>C	p.Pro4906Pro	synonymous	Exon 31 of 49	NP_002449.2	Q9HC84

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.14718T>C	p.Pro4906Pro	synonymous	Exon 31 of 49	ENSP00000436812.1	Q9HC84

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3223 AN: 152214 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0684

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0240 AC: 5940 AN: 247506 AF XY: 0.0241

Gnomad AFR exome AF: 0.00574

Gnomad AMR exome AF: 0.00453

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0737

Gnomad NFE exome AF: 0.0308

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0276 AC: 40301 AN: 1460638 Hom.: 732 Cov.: 78 AF XY: 0.0270 AC XY: 19632 AN XY: 726592

African (AFR) AF: 0.00341 AC: 114 AN: 33476

American (AMR) AF: 0.00499 AC: 223 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 632 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00936 AC: 807 AN: 86252

European-Finnish (FIN) AF: 0.0715 AC: 3753 AN: 52512

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.0299 AC: 33270 AN: 1111758

Other (OTH) AF: 0.0245 AC: 1477 AN: 60356

GnomAD4 genome AF: 0.0212 AC: 3224 AN: 152332 Hom.: 50 Cov.: 33 AF XY: 0.0218 AC XY: 1626 AN XY: 74492

African (AFR) AF: 0.00500 AC: 208 AN: 41576

American (AMR) AF: 0.00653 AC: 100 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4830

European-Finnish (FIN) AF: 0.0684 AC: 727 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0299 AC: 2033 AN: 68018

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.0259 Hom.: 25

Bravo AF: 0.0156

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0228

EpiControl AF: 0.0247

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.30
DANN	Benign	0.27
PhyloP100		-7.9
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: rs145066684; hg19: chr11-1272828;