19-8871627-C-T

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.42620G>A(p.Arg14207Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,588,182 control chromosomes in the GnomAD database, including 17 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (14 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.281

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=0.0040629804).
• BP6: Variant 19-8871627-C-T is Benign according to our data. Variant chr19-8871627-C-T is described in ClinVar as [Benign]. Clinvar id is 3038145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00419 (637/152174) while in subpopulation AFR AF= 0.0124 (513/41502). AF 95% confidence interval is 0.0115. There are 3 homozygotes in gnomad4. There are 309 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42194G>A	p.Arg14065Gln	missense_variant	79/93	ENST00000711671.1
MUC16	NM_001414686.1	c.42620G>A	p.Arg14207Gln	missense_variant	80/94
MUC16	NM_001414687.1	c.42074G>A	p.Arg14025Gln	missense_variant	76/90
MUC16	NM_024690.2	c.41972G>A	p.Arg13991Gln	missense_variant	70/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42158G>A	p.Arg14053Gln	missense_variant	74/88			A2

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 638 AN: 152056 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00228 AC: 511 AN: 224610 Hom.: 7 AF XY: 0.00238 AC XY: 290 AN XY: 121894

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.000958

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000789

Gnomad OTH exome AF: 0.00209

GnomAD4 exome AF: 0.00115 AC: 1649 AN: 1436008 Hom.: 14 Cov.: 32 AF XY: 0.00127 AC XY: 909 AN XY: 713570

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.00232

Gnomad4 ASJ exome AF: 0.000284

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00625

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000448

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00419 AC: 637 AN: 152174 Hom.: 3 Cov.: 31 AF XY: 0.00415 AC XY: 309 AN XY: 74414

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00475

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0103 AC: 43

ESP6500EA AF: 0.00107 AC: 9

ExAC AF: 0.00263 AC: 318

Asia WGS AF: 0.00289 AC: 10 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

Mar 14, 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	0.066
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	4.0
Dann	Benign	0.94
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.054
Sift	Benign	0.25	T
Sift4G	Benign	0.29	T
Vest4		0.095
MVP		0.085
ClinPred		0.013	T
GERP RS		-0.83
gMVP		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: rs114920126; hg19: chr19-8982303;