19-8876542-G-T

Position:

• chr19-8876542-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001414686.1(MUC16):​c.42517C>A​(p.Gln14173Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,612,852 control chromosomes in the GnomAD database, including 78,503 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 (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11034 hom., cov: 30)
  • Exomes 𝑓: 0.30 (67469 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.693

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0279218E-4).
• BP6: Variant 19-8876542-G-T is Benign according to our data. Variant chr19-8876542-G-T is described in ClinVar as [Benign]. Clinvar id is 3058901.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42091C>A	p.Gln14031Lys	missense_variant	77/93	ENST00000711671.1
MUC16	NM_001414686.1	c.42517C>A	p.Gln14173Lys	missense_variant	78/94
MUC16	NM_001414687.1	c.41971C>A	p.Gln13991Lys	missense_variant	74/90
MUC16	NM_024690.2	c.41869C>A	p.Gln13957Lys	missense_variant	68/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42055C>A	p.Gln14019Lys	missense_variant	72/88			A2

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55136 AN: 151782 Hom.: 11012 Cov.: 30

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.350

GnomAD3 exomes AF: 0.331 AC: 82294 AN: 248778 Hom.: 14705 AF XY: 0.336 AC XY: 45389 AN XY: 134938

Gnomad AFR exome AF: 0.547

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.401

Gnomad SAS exome AF: 0.478

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.285

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.295 AC: 431577 AN: 1460952 Hom.: 67469 Cov.: 54 AF XY: 0.301 AC XY: 218707 AN XY: 726746

Gnomad4 AFR exome AF: 0.560

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.324

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.273

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.363 AC: 55208 AN: 151900 Hom.: 11034 Cov.: 30 AF XY: 0.363 AC XY: 26957 AN XY: 74246

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.396

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.351

Alfa AF: 0.304 Hom.: 18838

Bravo AF: 0.370

TwinsUK AF: 0.264 AC: 978

ALSPAC AF: 0.271 AC: 1043

ESP6500AA AF: 0.513 AC: 2175

ESP6500EA AF: 0.272 AC: 2313

ExAC AF: 0.339 AC: 41020

Asia WGS AF: 0.425 AC: 1478 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.295

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MUC16-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.83
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.00010	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.15
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.055	T
Vest4		0.040
ClinPred		0.051	T
GERP RS		1.4
gMVP		0.48

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

Other links and lift over

dbSNP: rs3764556; hg19: chr19-8987218; COSMIC: COSV66689693;