chr11-1226228-C-T

Position:

• chr11-1226228-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002458.3(MUC5B):​c.151C>T​(p.Arg51Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0943 in 1,554,864 control chromosomes in the GnomAD database, including 9,376 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1434 hom., cov: 34)
  • Exomes 𝑓: 0.091 (7942 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.37

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.137358E-4).
• BP6: Variant 11-1226228-C-T is Benign according to our data. Variant chr11-1226228-C-T is described in ClinVar as [Benign]. Clinvar id is 163991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.151C>T	p.Arg51Trp	missense_variant	3/49	ENST00000529681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.151C>T	p.Arg51Trp	missense_variant	3/49	5	NM_002458.3	P1
MUC5B	ENST00000525715.5	n.209C>T		non_coding_transcript_exon_variant	3/26	1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18602 AN: 152128 Hom.: 1434 Cov.: 34

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.114 AC: 18549 AN: 163408 Hom.: 1608 AF XY: 0.112 AC XY: 9817 AN XY: 87324

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.0747

Gnomad ASJ exome AF: 0.0510

Gnomad EAS exome AF: 0.364

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.0971

GnomAD4 exome AF: 0.0913 AC: 128044 AN: 1402618 Hom.: 7942 Cov.: 33 AF XY: 0.0910 AC XY: 63055 AN XY: 692624

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0789

Gnomad4 ASJ exome AF: 0.0512

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.0751

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.122 AC: 18612 AN: 152246 Hom.: 1434 Cov.: 34 AF XY: 0.127 AC XY: 9482 AN XY: 74434

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.0536

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.0762

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0836 Hom.: 969

Bravo AF: 0.120

TwinsUK AF: 0.0715 AC: 265

ALSPAC AF: 0.0776 AC: 299

ESP6500AA AF: 0.141 AC: 551

ESP6500EA AF: 0.0699 AC: 569

ExAC AF: 0.0678 AC: 7345

Asia WGS AF: 0.270 AC: 940 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Arg51Trp in exon 3 of MUC5B: This variant is not expected to have clinical signi ficance because it has been identified in 14.1% (551/3908) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs2075853). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.72
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.00071	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.016
Sift	Benign	0.095	T
Polyphen		0.0020	B
Vest4		0.17
ClinPred		0.0055	T
GERP RS		-3.3
Varity_R		0.035
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2075853; hg19: chr11-1247458; COSMIC: COSV71590553; COSMIC: COSV71590553;