rs2943512

Positions:

• chr11-1250996-A-C
• chr11-1250996-A-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.14116A>C​(p.Thr4706Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,586,920 control chromosomes in the GnomAD database, including 214,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.52 (20589 hom., cov: 30)
  • Exomes 𝑓: 0.51 (194106 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.82

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=2.664287E-6).
• BP6: Variant 11-1250996-A-C is Benign according to our data. Variant chr11-1250996-A-C is described in ClinVar as [Benign]. Clinvar id is 403179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.14116A>C	p.Thr4706Pro	missense_variant	31/49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.14116A>C	p.Thr4706Pro	missense_variant	31/49	5	NM_002458.3	ENSP00000436812	P1

Frequencies

GnomAD3 genomes AF: 0.517 AC: 76729 AN: 148530 Hom.: 20554 Cov.: 30

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.520

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.527

GnomAD3 exomes AF: 0.532 AC: 130899 AN: 246148 Hom.: 36681 AF XY: 0.526 AC XY: 70341 AN XY: 133722

Gnomad AFR exome AF: 0.492

Gnomad AMR exome AF: 0.620

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.665

Gnomad SAS exome AF: 0.502

Gnomad FIN exome AF: 0.549

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.507 AC: 729107 AN: 1438268 Hom.: 194106 Cov.: 109 AF XY: 0.506 AC XY: 362192 AN XY: 715934

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.701

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.547

Gnomad4 NFE exome AF: 0.494

Gnomad4 OTH exome AF: 0.508

GnomAD4 genome AF: 0.517 AC: 76814 AN: 148652 Hom.: 20589 Cov.: 30 AF XY: 0.522 AC XY: 37875 AN XY: 72526

Gnomad4 AFR AF: 0.500

Gnomad4 AMR AF: 0.584

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.664

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.565

Gnomad4 NFE AF: 0.492

Gnomad4 OTH AF: 0.531

Alfa AF: 0.457 Hom.: 4941

Bravo AF: 0.516

TwinsUK AF: 0.487 AC: 1805

ALSPAC AF: 0.486 AC: 1873

ESP6500AA AF: 0.463 AC: 1966

ESP6500EA AF: 0.473 AC: 3991

ExAC AF: 0.520 AC: 62813

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.027
DANN	Benign	0.50
DEOGEN2	Benign	0.030	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.083
Sift	Benign	1.0	T
Vest4		0.010
ClinPred		0.0019	T
GERP RS		-3.2
Varity_R		0.047
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs2943512; hg19: chr11-1272226; COSMIC: COSV71594159; COSMIC: COSV71594159;