rs183657141

Positions:

• chr11-1242702-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.5822C>G​(p.Thr1941Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,613,430 control chromosomes in the GnomAD database, including 10 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (6 hom., cov: 32)
  • Exomes 𝑓: 0.030 (4 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.245

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=0.0031417608).
• BP6: Variant 11-1242702-C-G is Benign according to our data. Variant chr11-1242702-C-G is described in ClinVar as [Benign]. Clinvar id is 403132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0246 (3741/151826) while in subpopulation NFE AF= 0.0323 (2195/67856). AF 95% confidence interval is 0.0312. There are 6 homozygotes in gnomad4. There are 1865 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3741 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.5822C>G	p.Thr1941Ser	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.57-64G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.5822C>G	p.Thr1941Ser	missense_variant	31/49	5	NM_002458.3	ENSP00000436812	P1
MUC5B-AS1	ENST00000532061.2	n.57-64G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3742 AN: 151708 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00748

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00811

Gnomad FIN AF: 0.0673

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0226

GnomAD3 exomes AF: 0.0262 AC: 6524 AN: 249252 Hom.: 0 AF XY: 0.0259 AC XY: 3501 AN XY: 135228

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.00513

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00925

Gnomad FIN exome AF: 0.0720

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0296 AC: 43274 AN: 1461604 Hom.: 4 Cov.: 107 AF XY: 0.0290 AC XY: 21078 AN XY: 727100

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00934

Gnomad4 FIN exome AF: 0.0700

Gnomad4 NFE exome AF: 0.0321

Gnomad4 OTH exome AF: 0.0269

GnomAD4 genome AF: 0.0246 AC: 3741 AN: 151826 Hom.: 6 Cov.: 32 AF XY: 0.0251 AC XY: 1865 AN XY: 74206

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.00747

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00812

Gnomad4 FIN AF: 0.0673

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0224

Alfa AF: 0.0303 Hom.: 1

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0317 AC: 122

ESP6500AA AF: 0.0131 AC: 57

ESP6500EA AF: 0.0315 AC: 268

ExAC AF: 0.0273 AC: 3306

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.1
DANN	Benign	0.67
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.024
Sift	Benign	0.037	D
Vest4		0.027
ClinPred		0.00013	T
GERP RS		1.2
Varity_R		0.042
gMVP		0.26

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: rs183657141; hg19: chr11-1263932;