chr11-1247283-G-C

Variant names:

• chr11-1247283-G-C
• rs2943529
• NM_002458.3:c.10403G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002458.3(MUC5B):​c.10403G>C​(p.Arg3468Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,599,462 control chromosomes in the GnomAD database, including 187,111 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3468C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (17280 hom., cov: 32)
  • Exomes 𝑓: 0.48 (169831 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.88
• Publications: 17 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=4.8240413E-6).
• BP6: Variant 11-1247283-G-C is Benign according to our data. Variant chr11-1247283-G-C is described in ClinVar as Benign. ClinVar VariationId is 403161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

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.10403G>C	p.Arg3468Pro	missense	Exon 31 of 49	NP_002449.2
	MUC5B-AS1	NR_157183.1		n.56+2338C>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.10403G>C	p.Arg3468Pro	missense	Exon 31 of 49	ENSP00000436812.1
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.56+2338C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.472 AC: 70378 AN: 149252 Hom.: 17259 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.485

GnomAD2 exomes AF: 0.505 AC: 123513 AN: 244588 AF XY: 0.497

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.661

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.493

GnomAD4 exome AF: 0.478 AC: 692579 AN: 1450090 Hom.: 169831 Cov.: 192 AF XY: 0.475 AC XY: 342928 AN XY: 721336

African (AFR) AF: 0.389 AC: 12957 AN: 33310

American (AMR) AF: 0.591 AC: 26338 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 11683 AN: 25852

East Asian (EAS) AF: 0.705 AC: 27995 AN: 39696

South Asian (SAS) AF: 0.435 AC: 37349 AN: 85770

European-Finnish (FIN) AF: 0.561 AC: 28945 AN: 51572

Middle Eastern (MID) AF: 0.452 AC: 2035 AN: 4502

European-Non Finnish (NFE) AF: 0.468 AC: 517040 AN: 1105156

Other (OTH) AF: 0.473 AC: 28237 AN: 59700

GnomAD4 genome AF: 0.472 AC: 70430 AN: 149372 Hom.: 17280 Cov.: 32 AF XY: 0.479 AC XY: 34945 AN XY: 72946

African (AFR) AF: 0.400 AC: 16346 AN: 40910

American (AMR) AF: 0.553 AC: 8391 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1574 AN: 3396

East Asian (EAS) AF: 0.663 AC: 3416 AN: 5154

South Asian (SAS) AF: 0.443 AC: 2108 AN: 4754

European-Finnish (FIN) AF: 0.578 AC: 5866 AN: 10156

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.467 AC: 31105 AN: 66556

Other (OTH) AF: 0.490 AC: 1020 AN: 2082

Alfa AF: 0.397 Hom.: 1967

Bravo AF: 0.470

ESP6500AA AF: 0.383 AC: 1603

ESP6500EA AF: 0.464 AC: 3901

ExAC AF: 0.497 AC: 60089

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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.8
DANN	Benign	0.60
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00019	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-1.9
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.0060
Sift	Benign	0.17	T
Vest4		0.013
ClinPred		0.0069	T
GERP RS		-0.59
Varity_R		0.10
gMVP		0.32
Mutation Taster		=99/1	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: rs2943529; hg19: chr11-1268513; COSMIC: COSV71594280;