11-1243593-T-C

Variant names:

• chr11-1243593-T-C
• rs4963031
• NM_002458.3:c.6713T>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.6713T>C​(p.Leu2238Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,589,440 control chromosomes in the GnomAD database, including 408,821 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 0.73 (39764 hom., cov: 23)
  • Exomes 𝑓: 0.71 (369057 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.04

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=1.5669541E-6).
• BP6: Variant 11-1243593-T-C is Benign according to our data. Variant chr11-1243593-T-C is described in ClinVar as [Benign]. Clinvar id is 403140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.6713T>C	p.Leu2238Pro	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.57-955A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.6713T>C	p.Leu2238Pro	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.57-955A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.731 AC: 107098 AN: 146430 Hom.: 39707 Cov.: 23

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.978

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.663

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.725

GnomAD3 exomes AF: 0.750 AC: 183972 AN: 245140 Hom.: 71290 AF XY: 0.745 AC XY: 99154 AN XY: 133106

Gnomad AFR exome AF: 0.752

Gnomad AMR exome AF: 0.845

Gnomad ASJ exome AF: 0.691

Gnomad EAS exome AF: 0.983

Gnomad SAS exome AF: 0.766

Gnomad FIN exome AF: 0.774

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.722

GnomAD4 exome AF: 0.707 AC: 1019938 AN: 1442890 Hom.: 369057 Cov.: 126 AF XY: 0.707 AC XY: 507721 AN XY: 717958

Gnomad4 AFR exome AF: 0.742

Gnomad4 AMR exome AF: 0.838

Gnomad4 ASJ exome AF: 0.684

Gnomad4 EAS exome AF: 0.978

Gnomad4 SAS exome AF: 0.763

Gnomad4 FIN exome AF: 0.775

Gnomad4 NFE exome AF: 0.683

Gnomad4 OTH exome AF: 0.720

GnomAD4 genome AF: 0.732 AC: 107216 AN: 146550 Hom.: 39764 Cov.: 23 AF XY: 0.740 AC XY: 52755 AN XY: 71300

Gnomad4 AFR AF: 0.748

Gnomad4 AMR AF: 0.785

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.978

Gnomad4 SAS AF: 0.764

Gnomad4 FIN AF: 0.793

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.729

Alfa AF: 0.695 Hom.: 15969

Bravo AF: 0.733

ESP6500AA AF: 0.649 AC: 2768

ESP6500EA AF: 0.564 AC: 4759

ExAC AF: 0.737 AC: 89217

Asia WGS AF: 0.857 AC: 2971 AN: 3466

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	0.042
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.48
DANN	Benign	0.40
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00031	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.0030
Sift	Benign	0.15	T
Vest4		0.011
ClinPred		0.0059	T
GERP RS		-0.50
Varity_R		0.041
gMVP		0.18

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: rs4963031; hg19: chr11-1264823; COSMIC: COSV71590542; COSMIC: COSV71590542;