chr11-1244556-C-T

Variant names:

• chr11-1244556-C-T
• rs60787297
• NM_002458.3:c.7676C>T

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.7676C>T​(p.Thr2559Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,601,592 control chromosomes in the GnomAD database, including 69,187 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2559A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.42 (12953 hom., cov: 25)
  • Exomes 𝑓: 0.38 (56234 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.90
• Publications: 13 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=2.851046E-5).
• BP6: Variant 11-1244556-C-T is Benign according to our data. Variant chr11-1244556-C-T is described in ClinVar as Benign. ClinVar VariationId is 403143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

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.7676C>T	p.Thr2559Met	missense	Exon 31 of 49	NP_002449.2
	MUC5B-AS1	NR_157183.1		n.57-1918G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.7676C>T	p.Thr2559Met	missense	Exon 31 of 49	ENSP00000436812.1
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.57-1918G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.417 AC: 61068 AN: 146584 Hom.: 12938 Cov.: 25

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.425

GnomAD2 exomes AF: 0.446 AC: 106515 AN: 238782 AF XY: 0.441

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.630

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.382 AC: 555675 AN: 1454898 Hom.: 56234 Cov.: 107 AF XY: 0.383 AC XY: 276877 AN XY: 723846

African (AFR) AF: 0.285 AC: 9516 AN: 33370

American (AMR) AF: 0.502 AC: 22147 AN: 44134

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 10015 AN: 26002

East Asian (EAS) AF: 0.659 AC: 26051 AN: 39522

South Asian (SAS) AF: 0.386 AC: 33128 AN: 85918

European-Finnish (FIN) AF: 0.459 AC: 24258 AN: 52802

Middle Eastern (MID) AF: 0.371 AC: 2109 AN: 5682

European-Non Finnish (NFE) AF: 0.366 AC: 404947 AN: 1107352

Other (OTH) AF: 0.391 AC: 23504 AN: 60116

GnomAD4 genome AF: 0.417 AC: 61108 AN: 146694 Hom.: 12953 Cov.: 25 AF XY: 0.423 AC XY: 30222 AN XY: 71366

African (AFR) AF: 0.313 AC: 12580 AN: 40230

American (AMR) AF: 0.521 AC: 7657 AN: 14700

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1440 AN: 3374

East Asian (EAS) AF: 0.633 AC: 2992 AN: 4726

South Asian (SAS) AF: 0.415 AC: 1884 AN: 4544

European-Finnish (FIN) AF: 0.502 AC: 5026 AN: 10014

Middle Eastern (MID) AF: 0.367 AC: 105 AN: 286

European-Non Finnish (NFE) AF: 0.426 AC: 28102 AN: 65928

Other (OTH) AF: 0.431 AC: 868 AN: 2016

Alfa AF: 0.333 Hom.: 1293

ExAC AF: 0.430 AC: 51773

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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: Gene associated with pulmonary fibrosis

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.2
DANN	Benign	0.50
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.000029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		-3.9
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.085
Sift	Uncertain	0.0040	D
Vest4		0.015
ClinPred		0.010	T
GERP RS		-3.8
Varity_R		0.017
gMVP		0.21
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: rs60787297; hg19: chr11-1265786; COSMIC: COSV71589896;