19-8871595-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001414686.1(MUC16):c.42652C>T(p.Leu14218Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00804 in 1,608,972 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.010 ( 55 hom., cov: 31)

Exomes 𝑓: 0.0078 ( 376 hom. )

Consequence

MUC16
NM_001414686.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.443

Variant links:

Genes affected

MUC16 (HGNC:15582): (mucin 16, cell surface associated) This gene encodes a protein that is a member of the mucin family. Mucins are high molecular weight, O-glycosylated proteins that play an important role in forming a protective mucous barrier, and are found on the apical surfaces of the epithelia. The encoded protein is a membrane-tethered mucin that contains an extracellular domain at its amino terminus, a large tandem repeat domain, and a transmembrane domain with a short cytoplasmic domain. The amino terminus is highly glycosylated, while the repeat region contains 156 amino acid repeats unit that are rich in serines, threonines, and prolines. Interspersed within the repeats are Sea urchin sperm protein Enterokinase and Agrin (SEA) modules, leucine-rich repeats and ankyrin (ANK) repeats. These regions together form the ectodomain, and there is a potential cleavage site found near an SEA module close to the transmembrane domain. This protein is thought to play a role in forming a barrier, protecting epithelial cells from pathogens. Products of this gene have been used as a marker for different cancers, with higher expression levels associated with poorer outcomes. [provided by RefSeq, May 2017]

MUC16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025821626).

BP6

Variant 19-8871595-G-A is Benign according to our data. Variant chr19-8871595-G-A is described in ClinVar as [Benign]. Clinvar id is 3059793.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
MUC16	NM_001414686.1 link	c.42652C>T	p.Leu14218Phe	missense_variant	Exon 80 of 94	NP_001401615.1
MUC16	NM_001401501.2 link	c.42226C>T	p.Leu14076Phe	missense_variant	Exon 79 of 93	NP_001388430.1
MUC16	NM_001414687.1 link	c.42106C>T	p.Leu14036Phe	missense_variant	Exon 76 of 90	NP_001401616.1
MUC16	NM_024690.2 link	c.42004C>T	p.Leu14002Phe	missense_variant	Exon 70 of 84	NP_078966.2	Q8WXI7B3KY81

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
MUC16	ENST00000710609.1 link	c.42124C>T	p.Leu14042Phe	missense_variant	Exon 73 of 87		ENSP00000518375.1
MUC16	ENST00000397910.8 link	c.42004C>T	p.Leu14002Phe	missense_variant	Exon 70 of 84	5	ENSP00000381008.2	Q8WXI7
MUC16	ENST00000710610.1 link	c.32830C>T	p.Leu10944Phe	missense_variant	Exon 72 of 86		ENSP00000518376.1

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1565

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0426

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.0974

Gnomad SAS

AF:

0.0549

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00814

GnomAD3 exomes

AF:

0.0225

AC:

5485

AN:

243608

Hom.:

198

AF XY:

0.0213

AC XY:

2810

AN XY:

132196

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.0655

Gnomad ASJ exome

AF:

0.00559

Gnomad EAS exome

AF:

0.0967

Gnomad SAS exome

AF:

0.0469

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000588

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.00780

AC:

11362

AN:

1456762

Hom.:

376

Cov.:

AF XY:

0.00875

AC XY:

6342

AN XY:

724610

show subpopulations

Gnomad4 AFR exome

AF:

0.000811

Gnomad4 AMR exome

AF:

0.0636

Gnomad4 ASJ exome

AF:

0.00547

Gnomad4 EAS exome

AF:

0.0883

Gnomad4 SAS exome

AF:

0.0467

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000327

Gnomad4 OTH exome

AF:

0.00905

GnomAD4 genome

AF:

0.0103

AC:

1569

AN:

152210

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

900

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.0430

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.0970

Gnomad4 SAS

AF:

0.0550

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00598

Hom.:

Bravo

AF:

0.0137

ESP6500AA

AF:

0.00194

AC:

ESP6500EA

AF:

0.000593

AC:

ExAC

AF:

0.0217

AC:

2623

Asia WGS

AF:

0.0550

AC:

193

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MUC16-related disorder

Benign:1

Jan 03, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.6

DANN

Uncertain

0.98

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.74

REVEL

Benign

0.062

Sift

Benign

0.48

Sift4G

Benign

0.17

Vest4

0.032

ClinPred

0.027

GERP RS

1.8

gMVP

0.091

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over