19-8868547-G-C

Position:

chr19-8868547-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001414686.1(MUC16):c.42796C>G(p.Pro14266Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,710 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.017 ( 53 hom., cov: 32)

Exomes 𝑓: 0.016 ( 397 hom. )

Consequence

MUC16
NM_001414686.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.67

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=0.0039281845).

BP6

Variant 19-8868547-G-C is Benign according to our data. Variant chr19-8868547-G-C is described in ClinVar as [Benign]. Clinvar id is 3038195.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2543/152216) while in subpopulation NFE AF= 0.0207 (1407/67990). AF 95% confidence interval is 0.0198. There are 53 homozygotes in gnomad4. There are 1389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
MUC16	NM_001414686.1 link	c.42796C>G	p.Pro14266Ala	missense_variant	81/94	NP_001401615.1
MUC16	NM_001401501.2 link	c.42370C>G	p.Pro14124Ala	missense_variant	80/93	NP_001388430.1
MUC16	NM_001414687.1 link	c.42250C>G	p.Pro14084Ala	missense_variant	77/90	NP_001401616.1
MUC16	NM_024690.2 link	c.42148C>G	p.Pro14050Ala	missense_variant	71/84	NP_078966.2	Q8WXI7B3KY81

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
MUC16	ENST00000710609.1 link	c.42268C>G	p.Pro14090Ala	missense_variant	74/87		ENSP00000518375.1
MUC16	ENST00000397910.8 link	c.42148C>G	p.Pro14050Ala	missense_variant	71/84	5	ENSP00000381008.2	Q8WXI7
MUC16	ENST00000710610.1 link	c.32974C>G	p.Pro10992Ala	missense_variant	73/86		ENSP00000518376.1

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2545

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0651

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0207

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0194

AC:

4834

AN:

249064

Hom.:

AF XY:

0.0200

AC XY:

2705

AN XY:

135102

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00722

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0179

Gnomad FIN exome

AF:

0.0624

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0227

GnomAD4 exome

AF:

0.0162

AC:

23678

AN:

1461494

Hom.:

397

Cov.:

AF XY:

0.0168

AC XY:

12243

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00752

Gnomad4 ASJ exome

AF:

0.0274

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0199

Gnomad4 FIN exome

AF:

0.0594

Gnomad4 NFE exome

AF:

0.0148

Gnomad4 OTH exome

AF:

0.0166

GnomAD4 genome

AF:

0.0167

AC:

2543

AN:

152216

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

1389

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.00889

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.0651

Gnomad4 NFE

AF:

0.0207

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00255

AC:

ESP6500EA

AF:

0.0162

AC:

134

ExAC

AF:

0.0187

AC:

2256

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0195

EpiControl

AF:

0.0164

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

Feb 19, 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

0.082

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.12

Sift

Benign

0.062

Sift4G

Uncertain

0.032

Vest4

0.072

ClinPred

0.035

GERP RS

3.2

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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