19-8862883-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001414686.1(MUC16):c.43405A>G(p.Thr14469Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,604,718 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (7 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.39

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=0.0069482327).
• BP6: Variant 19-8862883-T-C is Benign according to our data. Variant chr19-8862883-T-C is described in ClinVar as [Benign]. Clinvar id is 3033479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00543 (827/152232) while in subpopulation AFR AF= 0.0165 (687/41526). AF 95% confidence interval is 0.0155. There are 10 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42979A>G	p.Thr14327Ala	missense_variant	86/93	ENST00000711671.1
MUC16	NM_001414686.1	c.43405A>G	p.Thr14469Ala	missense_variant	87/94
MUC16	NM_001414687.1	c.42859A>G	p.Thr14287Ala	missense_variant	83/90
MUC16	NM_024690.2	c.42757A>G	p.Thr14253Ala	missense_variant	77/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42943A>G	p.Thr14315Ala	missense_variant	81/88			A2

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 821 AN: 152114 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00240 AC: 563 AN: 234794 Hom.: 1 AF XY: 0.00227 AC XY: 288 AN XY: 126724

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00869

Gnomad SAS exome AF: 0.00400

Gnomad FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.000226

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000982 AC: 1427 AN: 1452486 Hom.: 7 Cov.: 31 AF XY: 0.00104 AC XY: 753 AN XY: 721378

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00950

Gnomad4 SAS exome AF: 0.00363

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000912

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.00543 AC: 827 AN: 152232 Hom.: 10 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74418

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00119 Hom.: 3

Bravo AF: 0.00549

ESP6500AA AF: 0.0123 AC: 50

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.00257 AC: 311

Asia WGS AF: 0.00866 AC: 30 AN: 3478

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

Apr 25, 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	0.20
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.095
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Vest4		0.13
MVP		0.23
ClinPred		0.031	T
GERP RS		4.4
gMVP		0.24

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: rs61734967; hg19: chr19-8973559;