19-8851305-C-G

Position:

• chr19-8851305-C-G

Variant summary

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

The NM_001414686.1(MUC16):​c.44044G>C​(p.Val14682Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 1,613,002 control chromosomes in the GnomAD database, including 689,345 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 0.92 (63904 hom., cov: 29)
  • Exomes 𝑓: 0.93 (625441 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.233

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=6.8387624E-7).
• BP6: Variant 19-8851305-C-G is Benign according to our data. Variant chr19-8851305-C-G is described in ClinVar as [Benign]. Clinvar id is 3058931.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC16	NM_001414686.1	c.44044G>C	p.Val14682Leu	missense_variant	93/94		NP_001401615.1
MUC16	NM_001401501.2	c.43618G>C	p.Val14540Leu	missense_variant	92/93		NP_001388430.1
MUC16	NM_001414687.1	c.43498G>C	p.Val14500Leu	missense_variant	89/90		NP_001401616.1
MUC16	NM_024690.2	c.43396G>C	p.Val14466Leu	missense_variant	83/84		NP_078966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC16	ENST00000710609.1	c.43516G>C	p.Val14506Leu	missense_variant	86/87			ENSP00000518375.1
MUC16	ENST00000397910.8	c.43396G>C	p.Val14466Leu	missense_variant	83/84	5		ENSP00000381008.2
MUC16	ENST00000710610.1	c.34222G>C	p.Val11408Leu	missense_variant	85/86			ENSP00000518376.1

Frequencies

GnomAD3 genomes AF: 0.917 AC: 139342 AN: 152012 Hom.: 63867 Cov.: 29

Gnomad AFR AF: 0.909

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.960

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.945

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.927

Gnomad OTH AF: 0.914

GnomAD3 exomes AF: 0.919 AC: 228028 AN: 248236 Hom.: 104863 AF XY: 0.923 AC XY: 124316 AN XY: 134702

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.854

Gnomad ASJ exome AF: 0.958

Gnomad EAS exome AF: 0.906

Gnomad SAS exome AF: 0.945

Gnomad FIN exome AF: 0.922

Gnomad NFE exome AF: 0.931

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.925 AC: 1351545 AN: 1460872 Hom.: 625441 Cov.: 62 AF XY: 0.927 AC XY: 673443 AN XY: 726764

Gnomad4 AFR exome AF: 0.904

Gnomad4 AMR exome AF: 0.853

Gnomad4 ASJ exome AF: 0.958

Gnomad4 EAS exome AF: 0.913

Gnomad4 SAS exome AF: 0.945

Gnomad4 FIN exome AF: 0.921

Gnomad4 NFE exome AF: 0.927

Gnomad4 OTH exome AF: 0.926

GnomAD4 genome AF: 0.917 AC: 139437 AN: 152130 Hom.: 63904 Cov.: 29 AF XY: 0.915 AC XY: 68068 AN XY: 74366

Gnomad4 AFR AF: 0.909

Gnomad4 AMR AF: 0.888

Gnomad4 ASJ AF: 0.960

Gnomad4 EAS AF: 0.902

Gnomad4 SAS AF: 0.945

Gnomad4 FIN AF: 0.910

Gnomad4 NFE AF: 0.927

Gnomad4 OTH AF: 0.913

Alfa AF: 0.926 Hom.: 49302

Bravo AF: 0.912

TwinsUK AF: 0.924 AC: 3427

ALSPAC AF: 0.931 AC: 3587

ESP6500AA AF: 0.915 AC: 3657

ESP6500EA AF: 0.931 AC: 7765

ExAC AF: 0.921 AC: 111321

Asia WGS AF: 0.905 AC: 3149 AN: 3478

EpiCase AF: 0.933

EpiControl AF: 0.934

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	0.066
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.10
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	6.8e-7	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.035
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.032
ClinPred		0.00030	T
GERP RS		-0.19
gMVP		0.19

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: rs1035442; hg19: chr19-8961981;