19-8865686-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.43114G>A(p.Gly14372Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,598,282 control chromosomes in the GnomAD database, including 5 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 0.00067 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.877

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=0.0073460042).
• BP6: Variant 19-8865686-C-T is Benign according to our data. Variant chr19-8865686-C-T is described in ClinVar as [Benign]. Clinvar id is 3040472.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00067 (102/152218) while in subpopulation EAS AF= 0.0114 (59/5158). AF 95% confidence interval is 0.0091. There are 2 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42688G>A	p.Gly14230Arg	missense_variant	84/93	ENST00000711671.1
MUC16	NM_001414686.1	c.43114G>A	p.Gly14372Arg	missense_variant	85/94
MUC16	NM_001414687.1	c.42568G>A	p.Gly14190Arg	missense_variant	81/90
MUC16	NM_024690.2	c.42466G>A	p.Gly14156Arg	missense_variant	75/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42652G>A	p.Gly14218Arg	missense_variant	79/88			A2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152100 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00124 AC: 288 AN: 232844 Hom.: 2 AF XY: 0.00142 AC XY: 180 AN XY: 126714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00911

Gnomad SAS exome AF: 0.00415

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.000358

GnomAD4 exome AF: 0.000535 AC: 773 AN: 1446064 Hom.: 3 Cov.: 31 AF XY: 0.000669 AC XY: 481 AN XY: 719172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000255

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.00937

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000524

Gnomad4 OTH exome AF: 0.000553

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152218 Hom.: 2 Cov.: 31 AF XY: 0.000779 AC XY: 58 AN XY: 74416

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.0000875 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00106 AC: 128

Asia WGS AF: 0.00722 AC: 25 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

Oct 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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	10
Dann	Benign	0.78
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.13
Sift	Benign	0.098	T
Sift4G	Benign	0.68	T
Vest4		0.16
MVP		0.21
ClinPred		0.048	T
GERP RS		0.43
gMVP		0.11

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: rs116913217; hg19: chr19-8976362;