Variant 19-8876400-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001414686.1(MUC16):c.42562C>T(p.Arg14188Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,448,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MUC16
NM_001414686.1 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.0690

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34239715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
MUC16	NM_001414686.1 link	c.42562C>T	p.Arg14188Trp	missense_variant	79/94	NP_001401615.1
MUC16	NM_001401501.2 link	c.42136C>T	p.Arg14046Trp	missense_variant	78/93	NP_001388430.1
MUC16	NM_001414687.1 link	c.42016C>T	p.Arg14006Trp	missense_variant	75/90	NP_001401616.1
MUC16	NM_024690.2 link	c.41914C>T	p.Arg13972Trp	missense_variant	69/84	NP_078966.2	Q8WXI7B3KY81

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
MUC16	ENST00000710609.1 link	c.42034C>T	p.Arg14012Trp	missense_variant	72/87		ENSP00000518375.1
MUC16	ENST00000397910.8 link	c.41914C>T	p.Arg13972Trp	missense_variant	69/84	5	ENSP00000381008.2	Q8WXI7
MUC16	ENST00000710610.1 link	c.32740C>T	p.Arg10914Trp	missense_variant	71/86		ENSP00000518376.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000442

AC:

AN:

225992

Hom.:

AF XY:

0.00000817

AC XY:

AN XY:

122338

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000981

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000552

AC:

AN:

1448900

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719404

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000388

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000633

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Congenital long QT syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genetics and Genomics Program, Sidra Medicine

The c.41914C>T missense variant in MUC16 is absent from population databases like gnomAD (PM2). ACMG codes: PM2, BP7. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.46

M_CAP

Benign

0.035

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.2

REVEL

Benign

0.093

Sift

Benign

0.13

Sift4G

Uncertain

0.025

Vest4

0.16

MVP

0.33

ClinPred

0.59

GERP RS

1.4

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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