rs4046509

Variant names:

• chr11-1245466-A-C
• rs4046509
• NM_002458.3:c.8586A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002458.3(MUC5B):​c.8586A>C​(p.Pro2862Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,095,550 control chromosomes in the GnomAD database, including 77,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (2950 hom., cov: 17)
  • Exomes 𝑓: 0.18 (77194 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC5B NM_002458.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.58
• Publications: 4 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BP6: Variant 11-1245466-A-C is Benign according to our data. Variant chr11-1245466-A-C is described in ClinVar as Benign. ClinVar VariationId is 403147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 77194 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.8586A>C	p.Pro2862Pro	synonymous	Exon 31 of 49	NP_002449.2	Q9HC84
	MUC5B-AS1	NR_157183.1		n.57-2828T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.8586A>C	p.Pro2862Pro	synonymous	Exon 31 of 49	ENSP00000436812.1	Q9HC84
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.57-2828T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.200 AC: 14723 AN: 73454 Hom.: 2947 Cov.: 17

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.266 AC: 44800 AN: 168454 AF XY: 0.260

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.361

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.575

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.178 AC: 194919 AN: 1095550 Hom.: 77194 Cov.: 41 AF XY: 0.184 AC XY: 100334 AN XY: 543980

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

African (AFR) AF: 0.192 AC: 4891 AN: 25488

American (AMR) AF: 0.298 AC: 8929 AN: 29926

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 5575 AN: 18950

East Asian (EAS) AF: 0.647 AC: 19717 AN: 30480

South Asian (SAS) AF: 0.258 AC: 15841 AN: 61354

European-Finnish (FIN) AF: 0.326 AC: 11847 AN: 36324

Middle Eastern (MID) AF: 0.258 AC: 786 AN: 3048

European-Non Finnish (NFE) AF: 0.138 AC: 116595 AN: 844784

Other (OTH) AF: 0.238 AC: 10738 AN: 45196

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.200 AC: 14737 AN: 73506 Hom.: 2950 Cov.: 17 AF XY: 0.193 AC XY: 6796 AN XY: 35228

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

African (AFR) AF: 0.175 AC: 3618 AN: 20650

American (AMR) AF: 0.226 AC: 1498 AN: 6632

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 377 AN: 1586

East Asian (EAS) AF: 0.458 AC: 1055 AN: 2306

South Asian (SAS) AF: 0.224 AC: 531 AN: 2374

European-Finnish (FIN) AF: 0.166 AC: 730 AN: 4394

Middle Eastern (MID) AF: 0.253 AC: 41 AN: 162

European-Non Finnish (NFE) AF: 0.193 AC: 6574 AN: 34006

Other (OTH) AF: 0.242 AC: 250 AN: 1034

⚠️ 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: 0.389 Hom.: 2638

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	2.1
DANN	Benign	0.60
PhyloP100		-3.6
Mutation Taster		=100/0	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: rs4046509; hg19: chr11-1266696; COSMIC: COSV71589778;