19-8871595-G-A

Position:

• chr19-8871595-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001414686.1(MUC16):​c.42652C>T​(p.Leu14218Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00804 in 1,608,972 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (55 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (376 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.443

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=0.0025821626).
• BP6: Variant 19-8871595-G-A is Benign according to our data. Variant chr19-8871595-G-A is described in ClinVar as [Benign]. Clinvar id is 3059793.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42226C>T	p.Leu14076Phe	missense_variant	79/93	ENST00000711671.1
MUC16	NM_001414686.1	c.42652C>T	p.Leu14218Phe	missense_variant	80/94
MUC16	NM_001414687.1	c.42106C>T	p.Leu14036Phe	missense_variant	76/90
MUC16	NM_024690.2	c.42004C>T	p.Leu14002Phe	missense_variant	70/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42190C>T	p.Leu14064Phe	missense_variant	74/88			A2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1565 AN: 152092 Hom.: 55 Cov.: 31

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.0974

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.0225 AC: 5485 AN: 243608 Hom.: 198 AF XY: 0.0213 AC XY: 2810 AN XY: 132196

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.0655

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.0967

Gnomad SAS exome AF: 0.0469

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000588

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.00780 AC: 11362 AN: 1456762 Hom.: 376 Cov.: 32 AF XY: 0.00875 AC XY: 6342 AN XY: 724610

Gnomad4 AFR exome AF: 0.000811

Gnomad4 AMR exome AF: 0.0636

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.0883

Gnomad4 SAS exome AF: 0.0467

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000327

Gnomad4 OTH exome AF: 0.00905

GnomAD4 genome AF: 0.0103 AC: 1569 AN: 152210 Hom.: 55 Cov.: 31 AF XY: 0.0121 AC XY: 900 AN XY: 74424

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.0430

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.0970

Gnomad4 SAS AF: 0.0550

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00598 Hom.: 78

Bravo AF: 0.0137

ESP6500AA AF: 0.00194 AC: 8

ESP6500EA AF: 0.000593 AC: 5

ExAC AF: 0.0217 AC: 2623

Asia WGS AF: 0.0550 AC: 193 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

Jan 03, 2020

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	0.089
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.6
DANN	Uncertain	0.98
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.062
Sift	Benign	0.48	T
Sift4G	Benign	0.17	T
Vest4		0.032
ClinPred		0.027	T
GERP RS		1.8
gMVP		0.091

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: rs3752141; hg19: chr19-8982271; COSMIC: COSV66689691; COSMIC: COSV66689691;