chr11-1226228-C-T

Variant names:

• chr11-1226228-C-T
• rs2075853
• NM_002458.3:c.151C>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.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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 27 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 (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 VariationId 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.

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.151C>T	p.Arg51Trp	missense	Exon 3 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.151C>T	p.Arg51Trp	missense	Exon 3 of 49	ENSP00000436812.1	Q9HC84
	MUC5B	ENST00000525715.5	TSL:1	n.209C>T		non_coding_transcript_exon	Exon 3 of 26

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

GnomAD2 exomes AF: 0.114 AC: 18549 AN: 163408 AF XY: 0.112

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 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

African (AFR) AF: 0.176 AC: 5585 AN: 31726

American (AMR) AF: 0.0789 AC: 2897 AN: 36722

Ashkenazi Jewish (ASJ) AF: 0.0512 AC: 1293 AN: 25252

East Asian (EAS) AF: 0.379 AC: 13606 AN: 35920

South Asian (SAS) AF: 0.128 AC: 10169 AN: 79446

European-Finnish (FIN) AF: 0.147 AC: 6844 AN: 46526

Middle Eastern (MID) AF: 0.0640 AC: 366 AN: 5716

European-Non Finnish (NFE) AF: 0.0751 AC: 81388 AN: 1083098

Other (OTH) AF: 0.101 AC: 5896 AN: 58212

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

African (AFR) AF: 0.171 AC: 7085 AN: 41546

American (AMR) AF: 0.100 AC: 1536 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0536 AC: 186 AN: 3472

East Asian (EAS) AF: 0.370 AC: 1912 AN: 5168

South Asian (SAS) AF: 0.141 AC: 679 AN: 4824

European-Finnish (FIN) AF: 0.153 AC: 1621 AN: 10600

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0762 AC: 5182 AN: 68014

Other (OTH) AF: 0.116 AC: 246 AN: 2116

Alfa AF: 0.0896 Hom.: 1912

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-1.4
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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