chr11-1234256-C-A

Position:

• chr11-1234256-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002458.3(MUC5B):​c.2429C>A​(p.Thr810Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,607,108 control chromosomes in the GnomAD database, including 8 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.323

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033239126).
• BP6: Variant 11-1234256-C-A is Benign according to our data. Variant chr11-1234256-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 178789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 593 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.2429C>A	p.Thr810Asn	missense_variant	20/49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.2429C>A	p.Thr810Asn	missense_variant	20/49	5	NM_002458.3	ENSP00000436812.1
MUC5B	ENST00000525715.5	n.2487C>A		non_coding_transcript_exon_variant	20/26	1

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152146 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000824

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00197 AC: 460 AN: 232956 Hom.: 3 AF XY: 0.00166 AC XY: 213 AN XY: 128118

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.00366

Gnomad EAS exome AF: 0.0000568

Gnomad SAS exome AF: 0.000103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000977

Gnomad OTH exome AF: 0.00384

GnomAD4 exome AF: 0.00114 AC: 1655 AN: 1454844 Hom.: 4 Cov.: 34 AF XY: 0.00114 AC XY: 821 AN XY: 723164

Gnomad4 AFR exome AF: 0.00977

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.00332

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000759

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00389 AC: 593 AN: 152264 Hom.: 4 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74456

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000824

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00462

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00817 AC: 32

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.00185 AC: 222

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Thr810Asn in exon 20 of MUC5B: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (32/3916) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs190624357). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.6
DANN	Benign	0.36
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.059
Sift	Benign	0.37	T
Polyphen		0.38	B
Vest4		0.18
MVP		0.20
ClinPred		0.015	T
GERP RS		-4.2
Varity_R		0.060
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs190624357; hg19: chr11-1255486;