19-8871536-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001414686.1(MUC16):c.42711T>C(p.His14237=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,605,734 control chromosomes in the GnomAD database, including 525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (49 hom., cov: 31)
  • Exomes 𝑓: 0.023 (476 hom.)
• Consequence: MUC16 NM_001414686.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -8.12

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-8871536-A-G is Benign according to our data. Variant chr19-8871536-A-G is described in ClinVar as [Benign]. Clinvar id is 3056808.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-8.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0223 (3387/152158) while in subpopulation AFR AF= 0.0287 (1193/41506). AF 95% confidence interval is 0.0274. There are 49 homozygotes in gnomad4. There are 1599 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42285T>C	p.His14095=	synonymous_variant	79/93	ENST00000711671.1
MUC16	NM_001414686.1	c.42711T>C	p.His14237=	synonymous_variant	80/94
MUC16	NM_001414687.1	c.42165T>C	p.His14055=	synonymous_variant	76/90
MUC16	NM_024690.2	c.42063T>C	p.His14021=	synonymous_variant	70/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42249T>C	p.His14083=	synonymous_variant	74/88			A2

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3370 AN: 152040 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0187 AC: 4511 AN: 241286 Hom.: 51 AF XY: 0.0194 AC XY: 2539 AN XY: 131132

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.00691

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00853

Gnomad SAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0231 AC: 33637 AN: 1453576 Hom.: 476 Cov.: 32 AF XY: 0.0233 AC XY: 16835 AN XY: 723062

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.00805

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.00975

Gnomad4 SAS exome AF: 0.0221

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0223 AC: 3387 AN: 152158 Hom.: 49 Cov.: 31 AF XY: 0.0215 AC XY: 1599 AN XY: 74396

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.0109

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.0241

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0231 Hom.: 22

Bravo AF: 0.0229

Asia WGS AF: 0.0180 AC: 61 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

Jun 28, 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
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.0040
Dann	Benign	0.34

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: rs78717907; hg19: chr19-8982212;