19-8863312-C-T

Position:

chr19-8863312-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBS2_Supporting

The NM_001414686.1(MUC16):c.43331G>A(p.Arg14444Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,605,806 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 12 hom. )

Consequence

MUC16
NM_001414686.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.138

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004735619).

BP6

Variant 19-8863312-C-T is Benign according to our data. Variant chr19-8863312-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2649216.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
MUC16	NM_001414686.1 link	c.43331G>A	p.Arg14444Lys	missense_variant	86/94	NP_001401615.1
MUC16	NM_001401501.2 link	c.42905G>A	p.Arg14302Lys	missense_variant	85/93	NP_001388430.1
MUC16	NM_001414687.1 link	c.42785G>A	p.Arg14262Lys	missense_variant	82/90	NP_001401616.1
MUC16	NM_024690.2 link	c.42683G>A	p.Arg14228Lys	missense_variant	76/84	NP_078966.2	Q8WXI7B3KY81

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
MUC16	ENST00000710609.1 link	c.42803G>A	p.Arg14268Lys	missense_variant	79/87		ENSP00000518375.1
MUC16	ENST00000397910.8 link	c.42683G>A	p.Arg14228Lys	missense_variant	76/84	5	ENSP00000381008.2	Q8WXI7
MUC16	ENST00000710610.1 link	c.33509G>A	p.Arg11170Lys	missense_variant	78/86		ENSP00000518376.1

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

447

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00347

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00320

AC:

753

AN:

235578

Hom.:

AF XY:

0.00300

AC XY:

381

AN XY:

127182

show subpopulations

Gnomad AFR exome

AF:

0.000698

Gnomad AMR exome

AF:

0.000275

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.00373

Gnomad OTH exome

AF:

0.00260

GnomAD4 exome

AF:

0.00326

AC:

4732

AN:

1453604

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2236

AN XY:

721990

show subpopulations

Gnomad4 AFR exome

AF:

0.000390

Gnomad4 AMR exome

AF:

0.000208

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0151

Gnomad4 NFE exome

AF:

0.00342

Gnomad4 OTH exome

AF:

0.00206

GnomAD4 genome

AF:

0.00294

AC:

447

AN:

152202

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

249

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0166

Gnomad4 NFE

AF:

0.00347

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00296

Hom.:

Bravo

AF:

0.00174

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000503

AC:

ESP6500EA

AF:

0.00385

AC:

ExAC

AF:

0.00322

AC:

389

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

MUC16: BP4, BS2 -

MUC16-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

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

0.11

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

9.2

DANN

Benign

0.96

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.60

REVEL

Benign

0.039

Sift

Benign

0.45

Sift4G

Benign

1.0

Vest4

0.091

MVP

0.25

ClinPred

0.015

GERP RS

2.4

gMVP

0.15

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