rs2547068

Positions:

chr19-8964541-T-A

Variant summary

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

The NM_001414686.1(MUC16):c.12775A>T(p.Thr4259Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,613,642 control chromosomes in the GnomAD database, including 68,895 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 Benign (no stars).

Frequency

Genomes: 𝑓 0.26 ( 5118 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63777 hom. )

Consequence

MUC16
NM_001414686.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.833

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=0.0038928986).

BP6

Variant 19-8964541-T-A is Benign according to our data. Variant chr19-8964541-T-A is described in ClinVar as [Benign]. Clinvar id is 3060874.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
MUC16	NM_001414686.1 linkuse as main transcript	c.12775A>T	p.Thr4259Ser	missense_variant	7/94	NP_001401615.1
MUC16	NM_001401501.2 linkuse as main transcript	c.12349A>T	p.Thr4117Ser	missense_variant	6/93	NP_001388430.1
MUC16	NM_001414687.1 linkuse as main transcript	c.12229A>T	p.Thr4077Ser	missense_variant	3/90	NP_001401616.1
MUC16	NM_024690.2 linkuse as main transcript	c.12229A>T	p.Thr4077Ser	missense_variant	3/84	NP_078966.2	Q8WXI7B3KY81

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
MUC16	ENST00000710609.1 linkuse as main transcript	c.12349A>T	p.Thr4117Ser	missense_variant	6/87		ENSP00000518375.1
MUC16	ENST00000397910.8 linkuse as main transcript	c.12229A>T	p.Thr4077Ser	missense_variant	3/84	5	ENSP00000381008.2	Q8WXI7
MUC16	ENST00000710610.1 linkuse as main transcript	c.3055A>T	p.Thr1019Ser	missense_variant	5/86		ENSP00000518376.1

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

39002

AN:

151972

Hom.:

5112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.269

Gnomad ASJ

AF:

0.180

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.273

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.292

Gnomad OTH

AF:

0.262

GnomAD3 exomes

AF:

0.262

AC:

65287

AN:

248770

Hom.:

8838

AF XY:

0.267

AC XY:

36016

AN XY:

134934

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.174

Gnomad EAS exome

AF:

0.272

Gnomad SAS exome

AF:

0.282

Gnomad FIN exome

AF:

0.239

Gnomad NFE exome

AF:

0.291

Gnomad OTH exome

AF:

0.261

GnomAD4 exome

AF:

0.292

AC:

426712

AN:

1461552

Hom.:

63777

Cov.:

AF XY:

0.291

AC XY:

211872

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.199

Gnomad4 AMR exome

AF:

0.224

Gnomad4 ASJ exome

AF:

0.173

Gnomad4 EAS exome

AF:

0.240

Gnomad4 SAS exome

AF:

0.283

Gnomad4 FIN exome

AF:

0.237

Gnomad4 NFE exome

AF:

0.307

Gnomad4 OTH exome

AF:

0.280

GnomAD4 genome

AF:

0.257

AC:

39034

AN:

152090

Hom.:

5118

Cov.:

AF XY:

0.253

AC XY:

18811

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.201

Gnomad4 AMR

AF:

0.269

Gnomad4 ASJ

AF:

0.180

Gnomad4 EAS

AF:

0.265

Gnomad4 SAS

AF:

0.274

Gnomad4 FIN

AF:

0.239

Gnomad4 NFE

AF:

0.292

Gnomad4 OTH

AF:

0.259

Alfa

AF:

0.267

Hom.:

1870

Bravo

AF:

0.258

TwinsUK

AF:

0.316

AC:

1171

ALSPAC

AF:

0.322

AC:

1242

ESP6500AA

AF:

0.197

AC:

773

ESP6500EA

AF:

0.289

AC:

2394

ExAC

AF:

0.262

AC:

31615

Asia WGS

AF:

0.259

AC:

901

AN:

3474

EpiCase

AF:

0.286

EpiControl

AF:

0.288

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MUC16-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 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

0.16

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.5

DANN

Benign

0.30

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.96

REVEL

Benign

0.034

Sift

Benign

0.080

Sift4G

Uncertain

0.021

Vest4

0.012

MutPred

0.12

Gain of phosphorylation at T4077 (P = 0.0688);

ClinPred

0.0056

GERP RS

-0.16

gMVP

0.053

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