rs185838223

Variant names:

• chr11-1249417-G-C
• rs185838223
• NM_002458.3:c.12537G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-1249417-G-C
• chr11-1249417-G-T

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.12537G>C​(p.Gln4179His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,611,248 control chromosomes in the GnomAD database, including 3,306 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. Q4179R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.062 (348 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2958 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.21
• Publications: 6 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=0.002925545).
• BP6: Variant 11-1249417-G-C is Benign according to our data. Variant chr11-1249417-G-C is described in ClinVar as Benign. ClinVar VariationId is 403172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 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.12537G>C	p.Gln4179His	missense	Exon 31 of 49	NP_002449.2	Q9HC84
	MUC5B-AS1	NR_157183.1		n.56+204C>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.12537G>C	p.Gln4179His	missense	Exon 31 of 49	ENSP00000436812.1	Q9HC84
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.56+204C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9485 AN: 152076 Hom.: 348 Cov.: 32

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0950

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0536

GnomAD2 exomes AF: 0.0653 AC: 15984 AN: 244920 AF XY: 0.0605

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.0408

Gnomad EAS exome AF: 0.00106

Gnomad FIN exome AF: 0.0849

Gnomad NFE exome AF: 0.0522

Gnomad OTH exome AF: 0.0651

GnomAD4 exome AF: 0.0564 AC: 82339 AN: 1459054 Hom.: 2958 Cov.: 118 AF XY: 0.0558 AC XY: 40536 AN XY: 725810

African (AFR) AF: 0.0619 AC: 2066 AN: 33396

American (AMR) AF: 0.146 AC: 6525 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0376 AC: 982 AN: 26130

East Asian (EAS) AF: 0.00123 AC: 49 AN: 39698

South Asian (SAS) AF: 0.0512 AC: 4415 AN: 86164

European-Finnish (FIN) AF: 0.0825 AC: 4380 AN: 53098

Middle Eastern (MID) AF: 0.0442 AC: 183 AN: 4144

European-Non Finnish (NFE) AF: 0.0545 AC: 60599 AN: 1111570

Other (OTH) AF: 0.0522 AC: 3140 AN: 60164

GnomAD4 genome AF: 0.0623 AC: 9489 AN: 152194 Hom.: 348 Cov.: 32 AF XY: 0.0653 AC XY: 4861 AN XY: 74398

African (AFR) AF: 0.0634 AC: 2629 AN: 41494

American (AMR) AF: 0.109 AC: 1674 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5176

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4830

European-Finnish (FIN) AF: 0.0950 AC: 1008 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0531 AC: 3609 AN: 68002

Other (OTH) AF: 0.0531 AC: 112 AN: 2110

Alfa AF: 0.0556 Hom.: 51

Bravo AF: 0.0645

ESP6500AA AF: 0.0626 AC: 237

ESP6500EA AF: 0.0528 AC: 432

ExAC AF: 0.0598 AC: 7160

EpiCase AF: 0.0497

EpiControl AF: 0.0465

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.52
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.039	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N
PhyloP100		-1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.076
Sift	Benign	0.51	T
Vest4		0.068
ClinPred		0.0027	T
GERP RS		-7.3
Varity_R		0.067
gMVP		0.72
Mutation Taster		=98/2	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: rs185838223; hg19: chr11-1270647; COSMIC: COSV106116112;