19-8868547-G-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.42796C>G(p.Pro14266Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,710 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (53 hom., cov: 32)
  • Exomes 𝑓: 0.016 (397 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67

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=0.0039281845).
• BP6: Variant 19-8868547-G-C is Benign according to our data. Variant chr19-8868547-G-C is described in ClinVar as [Benign]. Clinvar id is 3038195.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2543/152216) while in subpopulation NFE AF= 0.0207 (1407/67990). AF 95% confidence interval is 0.0198. There are 53 homozygotes in gnomad4. There are 1389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42370C>G	p.Pro14124Ala	missense_variant	80/93	ENST00000711671.1
MUC16	NM_001414686.1	c.42796C>G	p.Pro14266Ala	missense_variant	81/94
MUC16	NM_001414687.1	c.42250C>G	p.Pro14084Ala	missense_variant	77/90
MUC16	NM_024690.2	c.42148C>G	p.Pro14050Ala	missense_variant	71/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42334C>G	p.Pro14112Ala	missense_variant	75/88			A2

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2545 AN: 152098 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0194 AC: 4834 AN: 249064 Hom.: 89 AF XY: 0.0200 AC XY: 2705 AN XY: 135102

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00722

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0162 AC: 23678 AN: 1461494 Hom.: 397 Cov.: 31 AF XY: 0.0168 AC XY: 12243 AN XY: 727012

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00752

Gnomad4 ASJ exome AF: 0.0274

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0199

Gnomad4 FIN exome AF: 0.0594

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0167 AC: 2543 AN: 152216 Hom.: 53 Cov.: 32 AF XY: 0.0187 AC XY: 1389 AN XY: 74420

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.0651

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0201 Hom.: 41

Bravo AF: 0.0105

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00255 AC: 10

ESP6500EA AF: 0.0162 AC: 134

ExAC AF: 0.0187 AC: 2256

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0195

EpiControl AF: 0.0164

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 19, 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	0.082
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.12
Sift	Benign	0.062	T
Sift4G	Uncertain	0.032	D
Vest4		0.072
ClinPred		0.035	T
GERP RS		3.2
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144048376; hg19: chr19-8979223; COSMIC: COSV66689918; COSMIC: COSV66689918;