rs376986344

Variant names:

• chr11-1233015-A-G
• rs376986344
• NM_002458.3:c.2068A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002458.3(MUC5B):​c.2068A>G​(p.Lys690Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00007 in 1,586,486 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000032 (1 hom.)
• Consequence: MUC5B NM_002458.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.32

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028255492).
• BS2: High AC in GnomAd4 at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.2068A>G	p.Lys690Glu	missense_variant, splice_region_variant	Exon 18 of 49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.2068A>G	p.Lys690Glu	missense_variant, splice_region_variant	Exon 18 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B	ENST00000525715.5	n.2126A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 26	1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152190 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 24 AN: 214572 Hom.: 0 AF XY: 0.0000763 AC XY: 9 AN XY: 117992

Gnomad AFR exome AF: 0.00150

Gnomad AMR exome AF: 0.000155

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000321 AC: 46 AN: 1434178 Hom.: 1 Cov.: 34 AF XY: 0.0000253 AC XY: 18 AN XY: 711616

Gnomad4 AFR exome AF: 0.000967

Gnomad4 AMR exome AF: 0.0000935

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152308 Hom.: 0 Cov.: 34 AF XY: 0.000416 AC XY: 31 AN XY: 74470

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000665

ESP6500AA AF: 0.000469 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000158 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys690Glu variant in MUC5B has not been previously reported in individuals with pulmonary disease, but has been identified in 0.2% (9/3796) of African chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs376986344). Computational prediction tools and conservation analysis suggest that the p.Lys690Glu variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, the clini cal significance of the p.Lys690Glu variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Benign	0.73
DEOGEN2	Benign	0.048	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.30
Sift	Benign	0.038	D
Polyphen		0.99	D
Vest4		0.34
MVP		0.12
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.43
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376986344; hg19: chr11-1254245;