rs189329205

Variant names:

• chr11-1246061-T-C
• rs189329205
• NM_002458.3:c.9181T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.9181T>C​(p.Ser3061Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 148,444 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (78 hom., cov: 29)
  • Exomes 𝑓: 0.030 (923 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.55
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034552217).
• BP6: Variant 11-1246061-T-C is Benign according to our data. Variant chr11-1246061-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 403189.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 = 0.0257 (3816/148444) while in subpopulation NFE AF = 0.0332 (2228/67054). AF 95% confidence interval is 0.0321. There are 78 homozygotes in GnomAd4. There are 1898 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 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.9181T>C	p.Ser3061Pro	missense	Exon 31 of 49	NP_002449.2
	MUC5B-AS1	NR_157183.1		n.57-3423A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.9181T>C	p.Ser3061Pro	missense	Exon 31 of 49	ENSP00000436812.1
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.57-3423A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3817 AN: 148324 Hom.: 78 Cov.: 29

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000204

Gnomad SAS AF: 0.00842

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0332

Gnomad OTH AF: 0.0226

GnomAD2 exomes AF: 0.0267 AC: 6661 AN: 249048 AF XY: 0.0265

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.00513

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0280

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0302 AC: 44128 AN: 1461450 Hom.: 923 Cov.: 77 AF XY: 0.0295 AC XY: 21483 AN XY: 727008

African (AFR) AF: 0.0121 AC: 406 AN: 33468

American (AMR) AF: 0.00575 AC: 257 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 769 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00953 AC: 822 AN: 86248

European-Finnish (FIN) AF: 0.0729 AC: 3887 AN: 53340

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5766

European-Non Finnish (NFE) AF: 0.0326 AC: 36296 AN: 1111734

Other (OTH) AF: 0.0276 AC: 1664 AN: 60358

GnomAD4 genome AF: 0.0257 AC: 3816 AN: 148444 Hom.: 78 Cov.: 29 AF XY: 0.0262 AC XY: 1898 AN XY: 72400

African (AFR) AF: 0.0137 AC: 547 AN: 39826

American (AMR) AF: 0.00766 AC: 115 AN: 15018

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 102 AN: 3430

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4894

South Asian (SAS) AF: 0.00843 AC: 39 AN: 4626

European-Finnish (FIN) AF: 0.0712 AC: 737 AN: 10358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0332 AC: 2228 AN: 67054

Other (OTH) AF: 0.0224 AC: 46 AN: 2054

Alfa AF: 0.0274 Hom.: 40

Bravo AF: 0.0200

ESP6500AA AF: 0.0122 AC: 51

ESP6500EA AF: 0.0239 AC: 201

ExAC AF: 0.0279 AC: 3382

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0070
DANN	Benign	0.41
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.68	N
PhyloP100		-5.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.016
Sift	Benign	0.26	T
Vest4		0.020
ClinPred		0.0085	T
GERP RS		-6.4
Varity_R		0.061
gMVP		0.14
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: rs189329205; hg19: chr11-1267291; COSMIC: COSV71590549;