19-8851713-G-A

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.43958C>T(p.Ser14653Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0388 in 1,462,842 control chromosomes in the GnomAD database, including 1,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (71 hom., cov: 30)
  • Exomes 𝑓: 0.040 (1165 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.06

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=0.0039216876).
• BP6: Variant 19-8851713-G-A is Benign according to our data. Variant chr19-8851713-G-A is described in ClinVar as [Benign]. Clinvar id is 3056717.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0273 (4054/148482) while in subpopulation NFE AF= 0.0437 (2931/67058). AF 95% confidence interval is 0.0424. There are 71 homozygotes in gnomad4. There are 1897 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 72 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.43532C>T	p.Ser14511Phe	missense_variant	91/93	ENST00000711671.1
MUC16	NM_001414686.1	c.43958C>T	p.Ser14653Phe	missense_variant	92/94
MUC16	NM_001414687.1	c.43412C>T	p.Ser14471Phe	missense_variant	88/90
MUC16	NM_024690.2	c.43310C>T	p.Ser14437Phe	missense_variant	82/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.43496C>T	p.Ser14499Phe	missense_variant	86/88			A2

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4055 AN: 148424 Hom.: 72 Cov.: 30

Gnomad AFR AF: 0.00766

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.00877

Gnomad EAS AF: 0.000205

Gnomad SAS AF: 0.00345

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0437

Gnomad OTH AF: 0.0274

GnomAD3 exomes AF: 0.0254 AC: 3968 AN: 156192 Hom.: 82 AF XY: 0.0249 AC XY: 2054 AN XY: 82598

Gnomad AFR exome AF: 0.00654

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00137

Gnomad SAS exome AF: 0.00329

Gnomad FIN exome AF: 0.0375

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0401 AC: 52671 AN: 1314360 Hom.: 1165 Cov.: 35 AF XY: 0.0392 AC XY: 25492 AN XY: 649902

Gnomad4 AFR exome AF: 0.00591

Gnomad4 AMR exome AF: 0.0200

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.00115

Gnomad4 SAS exome AF: 0.00363

Gnomad4 FIN exome AF: 0.0434

Gnomad4 NFE exome AF: 0.0469

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.0273 AC: 4054 AN: 148482 Hom.: 71 Cov.: 30 AF XY: 0.0263 AC XY: 1897 AN XY: 72070

Gnomad4 AFR AF: 0.00764

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.00877

Gnomad4 EAS AF: 0.000206

Gnomad4 SAS AF: 0.00346

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0437

Gnomad4 OTH AF: 0.0272

Alfa AF: 0.0368 Hom.: 186

Bravo AF: 0.0252

TwinsUK AF: 0.0402 AC: 149

ALSPAC AF: 0.0467 AC: 180

ESP6500AA AF: 0.00990 AC: 35

ESP6500EA AF: 0.0352 AC: 275

ExAC AF: 0.0120 AC: 953

Asia WGS AF: 0.00375 AC: 13 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

Feb 26, 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	0.21
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Vest4		0.11
ClinPred		0.030	T
GERP RS		3.8
gMVP		0.74

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

Other links and lift over

dbSNP: rs72999925; hg19: chr19-8962389;