rs184215485

Variant names:

• chr11-1246506-G-A
• rs184215485
• NM_002458.3:c.9626G>A

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.9626G>A​(p.Arg3209Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 150,046 control chromosomes in the GnomAD database, including 68 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 (68 hom., cov: 32)
  • Exomes 𝑓: 0.026 (907 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.15
• Publications: 4 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-AS1 (HGNC:53936): (MUC5B antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038914084).
• BP6: Variant 11-1246506-G-A is Benign according to our data. Variant chr11-1246506-G-A is described in ClinVar as Benign. ClinVar VariationId is 403157.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 = 0.0253 (3799/150046) while in subpopulation NFE AF = 0.033 (2222/67358). AF 95% confidence interval is 0.0318. There are 68 homozygotes in GnomAd4. There are 1875 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.9626G>A	p.Arg3209Lys	missense	Exon 31 of 49	NP_002449.2
	MUC5B-AS1	NR_157183.1		n.56+3115C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.9626G>A	p.Arg3209Lys	missense	Exon 31 of 49	ENSP00000436812.1
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.56+3115C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3800 AN: 149924 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00840

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000403

Gnomad SAS AF: 0.00772

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0223

GnomAD2 exomes AF: 0.00978 AC: 2370 AN: 242354 AF XY: 0.00905

Gnomad AFR exome AF: 0.00726

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00569

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0434

Gnomad NFE exome AF: 0.00996

Gnomad OTH exome AF: 0.0110

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0257 AC: 37187 AN: 1447650 Hom.: 907 Cov.: 126 AF XY: 0.0251 AC XY: 18060 AN XY: 720182

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

African (AFR) AF: 0.0110 AC: 366 AN: 33310

American (AMR) AF: 0.00480 AC: 214 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 602 AN: 25818

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00772 AC: 663 AN: 85914

European-Finnish (FIN) AF: 0.0681 AC: 3589 AN: 52680

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5758

European-Non Finnish (NFE) AF: 0.0276 AC: 30327 AN: 1100088

Other (OTH) AF: 0.0234 AC: 1400 AN: 59838

⚠️ 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 AF: 0.0253 AC: 3799 AN: 150046 Hom.: 68 Cov.: 32 AF XY: 0.0256 AC XY: 1875 AN XY: 73240

African (AFR) AF: 0.0134 AC: 548 AN: 40798

American (AMR) AF: 0.00839 AC: 127 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 99 AN: 3436

East Asian (EAS) AF: 0.000404 AC: 2 AN: 4948

South Asian (SAS) AF: 0.00773 AC: 36 AN: 4660

European-Finnish (FIN) AF: 0.0688 AC: 718 AN: 10438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0330 AC: 2222 AN: 67358

Other (OTH) AF: 0.0221 AC: 46 AN: 2086

Alfa AF: 0.0303 Hom.: 18

Bravo AF: 0.0204

ExAC AF: 0.0228 AC: 2770

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0020
DANN	Benign	0.36
DEOGEN2	Benign	0.016	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.00030	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-5.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.0030
Sift	Benign	0.93	T
Vest4		0.0030
ClinPred		0.0047	T
GERP RS		-1.8
Varity_R		0.040
gMVP		0.17
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: rs184215485; hg19: chr11-1267736; COSMIC: COSV106116135;