11-1243512-G-C

Variant names:

• chr11-1243512-G-C
• rs137973688
• NM_002458.3:c.6632G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002458.3(MUC5B):​c.6632G>C​(p.Arg2211Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 1,433,604 control chromosomes in the GnomAD database, including 176,584 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2211C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (9470 hom., cov: 20)
  • Exomes 𝑓: 0.47 (167114 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.670
• Publications: 19 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-AS1 (HGNC:53936): (MUC5B antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.529953E-4).
• BP6: Variant 11-1243512-G-C is Benign according to our data. Variant chr11-1243512-G-C is described in ClinVar as Benign. ClinVar VariationId is 403139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9470 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.6632G>C	p.Arg2211Pro	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.57-874C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.6632G>C	p.Arg2211Pro	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.57-874C>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.375 AC: 43160 AN: 115034 Hom.: 9453 Cov.: 20

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.409 AC: 88330 AN: 216070 AF XY: 0.405

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.634

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.469 AC: 618418 AN: 1318450 Hom.: 167114 Cov.: 116 AF XY: 0.466 AC XY: 306146 AN XY: 656660

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.319 AC: 10174 AN: 31872

American (AMR) AF: 0.589 AC: 25643 AN: 43512

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 10655 AN: 24200

East Asian (EAS) AF: 0.709 AC: 27459 AN: 38724

South Asian (SAS) AF: 0.427 AC: 34645 AN: 81080

European-Finnish (FIN) AF: 0.551 AC: 26445 AN: 48012

Middle Eastern (MID) AF: 0.422 AC: 1657 AN: 3924

European-Non Finnish (NFE) AF: 0.460 AC: 456260 AN: 991944

Other (OTH) AF: 0.462 AC: 25480 AN: 55182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.375 AC: 43209 AN: 115154 Hom.: 9470 Cov.: 20 AF XY: 0.383 AC XY: 21317 AN XY: 55708

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.264 AC: 8678 AN: 32858

American (AMR) AF: 0.487 AC: 5782 AN: 11870

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1039 AN: 2660

East Asian (EAS) AF: 0.553 AC: 1619 AN: 2928

South Asian (SAS) AF: 0.351 AC: 1213 AN: 3460

European-Finnish (FIN) AF: 0.506 AC: 3838 AN: 7580

Middle Eastern (MID) AF: 0.333 AC: 86 AN: 258

European-Non Finnish (NFE) AF: 0.391 AC: 20041 AN: 51320

Other (OTH) AF: 0.385 AC: 594 AN: 1544

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.311 Hom.: 1010

ExAC AF: 0.408 AC: 49352

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	0.062
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.0
DANN	Benign	0.50
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00017	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.00045	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.67
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.047
Sift	Benign	0.17	T
Vest4		0.023
ClinPred		0.00058	T
GERP RS		1.8
Varity_R		0.099
gMVP		0.28
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs137973688; hg19: chr11-1264742; COSMIC: COSV71589895; COSMIC: COSV71589895;