11-1246497-T-C

Variant names:

• chr11-1246497-T-C
• rs202001610
• NM_002458.3:c.9617T>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.9617T>C​(p.Ile3206Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,602,608 control chromosomes in the GnomAD database, including 962 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (69 hom., cov: 32)
  • Exomes 𝑓: 0.028 (893 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.907
• Publications: 3 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=0.0043921173).
• BP6: Variant 11-1246497-T-C is Benign according to our data. Variant chr11-1246497-T-C is described in ClinVar as Benign. ClinVar VariationId is 403156.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 (3763/146368) while in subpopulation NFE AF = 0.0333 (2201/66084). AF 95% confidence interval is 0.0321. There are 69 homozygotes in GnomAd4. There are 1868 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 69 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.9617T>C	p.Ile3206Thr	missense	Exon 31 of 49	NP_002449.2	Q9HC84
	MUC5B-AS1	NR_157183.1		n.56+3124A>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.9617T>C	p.Ile3206Thr	missense	Exon 31 of 49	ENSP00000436812.1	Q9HC84
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.56+3124A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3764 AN: 146234 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.00780

Gnomad ASJ AF: 0.0295

Gnomad EAS AF: 0.000421

Gnomad SAS AF: 0.00799

Gnomad FIN AF: 0.0708

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0228

GnomAD2 exomes AF: 0.00969 AC: 2336 AN: 240968 AF XY: 0.00901

Gnomad AFR exome AF: 0.00772

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0277 AC: 40384 AN: 1456240 Hom.: 893 Cov.: 127 AF XY: 0.0272 AC XY: 19730 AN XY: 724588

African (AFR) AF: 0.0113 AC: 376 AN: 33326

American (AMR) AF: 0.00537 AC: 240 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 720 AN: 26052

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00905 AC: 780 AN: 86162

European-Finnish (FIN) AF: 0.0708 AC: 3769 AN: 53202

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5756

European-Non Finnish (NFE) AF: 0.0297 AC: 32926 AN: 1107176

Other (OTH) AF: 0.0257 AC: 1546 AN: 60194

GnomAD4 genome AF: 0.0257 AC: 3763 AN: 146368 Hom.: 69 Cov.: 32 AF XY: 0.0261 AC XY: 1868 AN XY: 71490

African (AFR) AF: 0.0137 AC: 539 AN: 39412

American (AMR) AF: 0.00779 AC: 116 AN: 14888

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 99 AN: 3360

East Asian (EAS) AF: 0.000421 AC: 2 AN: 4748

South Asian (SAS) AF: 0.00800 AC: 36 AN: 4502

European-Finnish (FIN) AF: 0.0708 AC: 723 AN: 10214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 250

European-Non Finnish (NFE) AF: 0.0333 AC: 2201 AN: 66084

Other (OTH) AF: 0.0225 AC: 46 AN: 2042

Alfa AF: 0.0266 Hom.: 73

Bravo AF: 0.0199

ExAC AF: 0.0227 AC: 2749

ClinVar

ClinVar submissions

Significance: 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	0.067
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.18
DANN	Benign	0.46
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00032	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.3	N
PhyloP100		-0.91
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.73	N
REVEL	Benign	0.0050
Sift	Benign	1.0	T
Vest4		0.0060
ClinPred		0.0014	T
GERP RS		-2.4
Varity_R		0.029
gMVP		0.089
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: rs202001610; hg19: chr11-1267727; COSMIC: COSV71590696;