chr11-1244757-C-T

Variant names:

• chr11-1244757-C-T
• rs3021158
• NM_002458.3:c.7877C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002458.3(MUC5B):​c.7877C>T​(p.Thr2626Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00864 in 149,014 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2626R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0086 (7 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390
• Publications: 15 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005446613).
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.7877C>T	p.Thr2626Met	missense	Exon 31 of 49	NP_002449.2
	MUC5B-AS1	NR_157183.1		n.57-2119G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.7877C>T	p.Thr2626Met	missense	Exon 31 of 49	ENSP00000436812.1
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.57-2119G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00864 AC: 1286 AN: 148894 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00198

Gnomad ASJ AF: 0.00445

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00272

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00626

Gnomad OTH AF: 0.00732

GnomAD2 exomes AF: 0.00233 AC: 559 AN: 239454 AF XY: 0.00199

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.000496

Gnomad ASJ exome AF: 0.00156

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.00336

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00155

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00128 AC: 1778 AN: 1393864 Hom.: 5 Cov.: 141 AF XY: 0.00120 AC XY: 831 AN XY: 694168

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

African (AFR) AF: 0.0167 AC: 556 AN: 33256

American (AMR) AF: 0.000653 AC: 29 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.000523 AC: 13 AN: 24878

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.000247 AC: 21 AN: 84904

European-Finnish (FIN) AF: 0.00289 AC: 139 AN: 48168

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5680

European-Non Finnish (NFE) AF: 0.000875 AC: 923 AN: 1055052

Other (OTH) AF: 0.00142 AC: 82 AN: 57838

⚠️ 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: 0.00864 AC: 1287 AN: 149014 Hom.: 7 Cov.: 30 AF XY: 0.00858 AC XY: 625 AN XY: 72850

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

African (AFR) AF: 0.0163 AC: 671 AN: 41228

American (AMR) AF: 0.00198 AC: 30 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00445 AC: 15 AN: 3374

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00293 AC: 14 AN: 4774

European-Finnish (FIN) AF: 0.0129 AC: 129 AN: 10038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00626 AC: 413 AN: 65980

Other (OTH) AF: 0.00725 AC: 15 AN: 2070

⚠️ 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: 0.0161 Hom.: 160

ExAC AF: 0.0130 AC: 1571

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.61
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.039
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.055
Sift	Pathogenic	0.0	D
Vest4		0.071
ClinPred		0.014	T
GERP RS		0.12
Varity_R		0.046
gMVP		0.29
Mutation Taster		=100/0	polymorphism

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: rs3021158; hg19: chr11-1265987;