rs2591592

Positions:

• chr19-8964670-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001414686.1(MUC16):​c.12646A>T​(p.Ile4216Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,613,456 control chromosomes in the GnomAD database, including 257,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.51 (20447 hom., cov: 31)
  • Exomes 𝑓: 0.56 (237279 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.774

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.0184352E-5).
• BP6: Variant 19-8964670-T-A is Benign according to our data. Variant chr19-8964670-T-A is described in ClinVar as [Benign]. Clinvar id is 3059888.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC16	NM_001401501.2	c.12220A>T	p.Ile4074Phe	missense_variant	6/93	ENST00000711671.1	NP_001388430.1
MUC16	NM_001414686.1	c.12646A>T	p.Ile4216Phe	missense_variant	7/94		NP_001401615.1
MUC16	NM_001414687.1	c.12100A>T	p.Ile4034Phe	missense_variant	3/90		NP_001401616.1
MUC16	NM_024690.2	c.12100A>T	p.Ile4034Phe	missense_variant	3/84		NP_078966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC16	ENST00000711672.1	c.12220A>T	p.Ile4074Phe	missense_variant	6/88			ENSP00000518832	A2
MUC16	ENST00000710609.1	c.12220A>T	p.Ile4074Phe	missense_variant	6/87			ENSP00000518375	A2
MUC16	ENST00000397910.8	c.12100A>T	p.Ile4034Phe	missense_variant	3/84	5		ENSP00000381008	P2
MUC16	ENST00000710610.1	c.2926A>T	p.Ile976Phe	missense_variant	5/86			ENSP00000518376	A2

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77670 AN: 151844 Hom.: 20436 Cov.: 31

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.530

GnomAD3 exomes AF: 0.514 AC: 128058 AN: 248968 Hom.: 34079 AF XY: 0.524 AC XY: 70714 AN XY: 135036

Gnomad AFR exome AF: 0.411

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.572

Gnomad EAS exome AF: 0.276

Gnomad SAS exome AF: 0.534

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.535

GnomAD4 exome AF: 0.565 AC: 825171 AN: 1461494 Hom.: 237279 Cov.: 62 AF XY: 0.565 AC XY: 410413 AN XY: 727024

Gnomad4 AFR exome AF: 0.404

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.573

Gnomad4 EAS exome AF: 0.247

Gnomad4 SAS exome AF: 0.539

Gnomad4 FIN exome AF: 0.495

Gnomad4 NFE exome AF: 0.592

Gnomad4 OTH exome AF: 0.550

GnomAD4 genome AF: 0.511 AC: 77711 AN: 151962 Hom.: 20447 Cov.: 31 AF XY: 0.506 AC XY: 37600 AN XY: 74264

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.516

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.502

Gnomad4 FIN AF: 0.489

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.524

Alfa AF: 0.564 Hom.: 7866

Bravo AF: 0.507

TwinsUK AF: 0.611 AC: 2266

ALSPAC AF: 0.599 AC: 2308

ESP6500AA AF: 0.448 AC: 1807

ESP6500EA AF: 0.592 AC: 4917

ExAC AF: 0.515 AC: 62229

Asia WGS AF: 0.386 AC: 1343 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MUC16-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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	0.10
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.28
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.000030	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.023
Sift	Benign	0.75	T
Sift4G	Uncertain	0.025	D
Vest4		0.032
ClinPred		0.013	T
GERP RS		-1.1
gMVP		0.036

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: rs2591592; hg19: chr19-9075346; COSMIC: COSV67453691;