19-8871590-G-A

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.42657C>T(p.Ser14219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,608,516 control chromosomes in the GnomAD database, including 510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (40 hom., cov: 31)
  • Exomes 𝑓: 0.023 (470 hom.)
• Consequence: MUC16 NM_001414686.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -7.13

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=-0.89).
• BP6: Variant 19-8871590-G-A is Benign according to our data. Variant chr19-8871590-G-A is described in ClinVar as [Benign]. Clinvar id is 3056085.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-7.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0202 (3072/152178) while in subpopulation NFE AF= 0.024 (1634/67994). AF 95% confidence interval is 0.0231. There are 40 homozygotes in gnomad4. There are 1443 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42231C>T	p.Ser14077=	synonymous_variant	79/93	ENST00000711671.1
MUC16	NM_001414686.1	c.42657C>T	p.Ser14219=	synonymous_variant	80/94
MUC16	NM_001414687.1	c.42111C>T	p.Ser14037=	synonymous_variant	76/90
MUC16	NM_024690.2	c.42009C>T	p.Ser14003=	synonymous_variant	70/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42195C>T	p.Ser14065=	synonymous_variant	74/88			A2

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3070 AN: 152060 Hom.: 40 Cov.: 31

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0183 AC: 4459 AN: 243328 Hom.: 49 AF XY: 0.0191 AC XY: 2521 AN XY: 132108

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.00661

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00842

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0230 AC: 33447 AN: 1456338 Hom.: 470 Cov.: 32 AF XY: 0.0232 AC XY: 16772 AN XY: 724374

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.00776

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.00975

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0253

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0202 AC: 3072 AN: 152178 Hom.: 40 Cov.: 31 AF XY: 0.0194 AC XY: 1443 AN XY: 74396

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0226 Hom.: 20

Bravo AF: 0.0209

Asia WGS AF: 0.0140 AC: 48 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	-0.89
Cadd	Benign	0.016
Dann	Benign	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: rs76124866; hg19: chr19-8982266;