11-1243461-T-C

Variant names:

• chr11-1243461-T-C
• rs2943502
• NM_002458.3:c.6581T>C

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.6581T>C​(p.Met2194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,365,212 control chromosomes in the GnomAD database, including 339,665 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.74 (34222 hom., cov: 18)
  • Exomes 𝑓: 0.61 (305443 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.89

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5453392E-6).
• BP6: Variant 11-1243461-T-C is Benign according to our data. Variant chr11-1243461-T-C is described in ClinVar as [Benign]. Clinvar id is 403137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.6581T>C	p.Met2194Thr	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.57-823A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.6581T>C	p.Met2194Thr	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.57-823A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.743 AC: 82763 AN: 111388 Hom.: 34164 Cov.: 18

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.777

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.711

GnomAD3 exomes AF: 0.633 AC: 110404 AN: 174334 Hom.: 47122 AF XY: 0.618 AC XY: 58291 AN XY: 94384

Gnomad AFR exome AF: 0.901

Gnomad AMR exome AF: 0.805

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.963

Gnomad SAS exome AF: 0.688

Gnomad FIN exome AF: 0.638

Gnomad NFE exome AF: 0.476

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.615 AC: 770793 AN: 1253722 Hom.: 305443 Cov.: 95 AF XY: 0.618 AC XY: 384414 AN XY: 622490

Gnomad4 AFR exome AF: 0.918

Gnomad4 AMR exome AF: 0.835

Gnomad4 ASJ exome AF: 0.632

Gnomad4 EAS exome AF: 0.985

Gnomad4 SAS exome AF: 0.738

Gnomad4 FIN exome AF: 0.701

Gnomad4 NFE exome AF: 0.566

Gnomad4 OTH exome AF: 0.666

GnomAD4 genome AF: 0.743 AC: 82871 AN: 111490 Hom.: 34222 Cov.: 18 AF XY: 0.750 AC XY: 40414 AN XY: 53904

Gnomad4 AFR AF: 0.920

Gnomad4 AMR AF: 0.778

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.966

Gnomad4 SAS AF: 0.725

Gnomad4 FIN AF: 0.720

Gnomad4 NFE AF: 0.610

Gnomad4 OTH AF: 0.716

Alfa AF: 0.525 Hom.: 3027

ESP6500AA AF: 0.842 AC: 3120

ESP6500EA AF: 0.488 AC: 3886

ExAC AF: 0.569 AC: 57470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0040
DANN	Benign	0.40
DEOGEN2	Benign	0.014	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.00024	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.030
Sift	Benign	0.81	T
Vest4		0.021
ClinPred		0.0021	T
GERP RS		-4.5
Varity_R		0.038
gMVP		0.19

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: rs2943502; hg19: chr11-1264691; COSMIC: COSV71589887; COSMIC: COSV71589887;