rs190624357

Variant names:

• chr11-1234256-C-A
• rs190624357
• NM_002458.3:c.2429C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-1234256-C-A
• chr11-1234256-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002458.3(MUC5B):​c.2429C>A​(p.Thr810Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,607,108 control chromosomes in the GnomAD database, including 8 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.323
• Publications: 0 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 Gene-Disease associations (from GenCC):

• interstitial lung disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033239126).
• BP6: Variant 11-1234256-C-A is Benign according to our data. Variant chr11-1234256-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178789.
• BS2: High Homozygotes in GnomAd4 at 4 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.2429C>A	p.Thr810Asn	missense	Exon 20 of 49	NP_002449.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.2429C>A	p.Thr810Asn	missense	Exon 20 of 49	ENSP00000436812.1
	MUC5B	ENST00000525715.5	TSL:1	n.2487C>A		non_coding_transcript_exon	Exon 20 of 26

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152146 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000824

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00197 AC: 460 AN: 232956 AF XY: 0.00166

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.00366

Gnomad EAS exome AF: 0.0000568

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000977

Gnomad OTH exome AF: 0.00384

GnomAD4 exome AF: 0.00114 AC: 1655 AN: 1454844 Hom.: 4 Cov.: 34 AF XY: 0.00114 AC XY: 821 AN XY: 723164

African (AFR) AF: 0.00977 AC: 326 AN: 33372

American (AMR) AF: 0.00429 AC: 190 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.00332 AC: 86 AN: 25884

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39596

South Asian (SAS) AF: 0.0000707 AC: 6 AN: 84838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51552

Middle Eastern (MID) AF: 0.00599 AC: 29 AN: 4842

European-Non Finnish (NFE) AF: 0.000759 AC: 843 AN: 1110494

Other (OTH) AF: 0.00287 AC: 172 AN: 60022

GnomAD4 genome AF: 0.00389 AC: 593 AN: 152264 Hom.: 4 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74456

African (AFR) AF: 0.0109 AC: 451 AN: 41542

American (AMR) AF: 0.00425 AC: 65 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000824 AC: 56 AN: 67990

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00186 Hom.: 1

Bravo AF: 0.00462

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00817 AC: 32

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.00185 AC: 222

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.6
DANN	Benign	0.36
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.32
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.059
Sift	Benign	0.37	T
Polyphen		0.38	B
Vest4		0.18
MVP		0.20
ClinPred		0.015	T
GERP RS		-4.2
Varity_R		0.060
gMVP		0.54
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs190624357; hg19: chr11-1255486;