rs200719329

chr11-1260703-G-Achr11-1260703-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002458.3(MUC5B):c.17044G>A(p.Glu5682Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000724 in 1,611,822 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.52

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017220527).
• BP6: Variant 11-1260703-G-A is Benign according to our data. Variant chr11-1260703-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227553.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.17044G>A	p.Glu5682Lys	missense_variant	48/49	ENST00000529681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.17044G>A	p.Glu5682Lys	missense_variant	48/49	5	NM_002458.3	P1
MUC5B	ENST00000526859.1	c.435+861G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000670 AC: 164 AN: 244846 Hom.: 1 AF XY: 0.000674 AC XY: 90 AN XY: 133480

Gnomad AFR exome AF: 0.0000665

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00299

Gnomad NFE exome AF: 0.000790

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000736 AC: 1074 AN: 1459464 Hom.: 2 Cov.: 32 AF XY: 0.000731 AC XY: 531 AN XY: 725914

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00242

Gnomad4 NFE exome AF: 0.000796

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000610 AC: 93 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74510

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000660 Hom.: 0

Bravo AF: 0.000382

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000356 AC: 3

ExAC AF: 0.000639 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 11, 2022	The c.17044G>A (p.E5682K) alteration is located in exon 48 (coding exon 48) of the MUC5B gene. This alteration results from a G to A substitution at nucleotide position 17044, causing the glutamic acid (E) at amino acid position 5682 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 11, 2015	p.Glu5682Lys in exon 48 of MUC5B: This variant is not expected to have clinical significance because it has been identified in 0.3% (15/5332) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200719329). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.17
Sift	Benign	0.063	T
Vest4		0.43
MVP		0.14
ClinPred		0.059	T
GERP RS		4.0
Varity_R		0.14
gMVP		0.72

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: rs200719329; hg19: chr11-1281933; COSMIC: COSV71592659; COSMIC: COSV71592659;