19-8858668-A-G

Position:

• chr19-8858668-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_001414686.1(MUC16):​c.43648T>C​(p.Tyr14550His) variant causes a missense change. The variant allele was found at a frequency of 0.00714 in 1,613,270 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (52 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.18

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011470199).
• BP6: Variant 19-8858668-A-G is Benign according to our data. Variant chr19-8858668-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2649214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00469 (712/151764) while in subpopulation NFE AF= 0.00783 (532/67936). AF 95% confidence interval is 0.00728. There are 3 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.43222T>C	p.Tyr14408His	missense_variant	88/93	ENST00000711671.1
MUC16	NM_001414686.1	c.43648T>C	p.Tyr14550His	missense_variant	89/94
MUC16	NM_001414687.1	c.43102T>C	p.Tyr14368His	missense_variant	85/90
MUC16	NM_024690.2	c.43000T>C	p.Tyr14334His	missense_variant	79/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.43186T>C	p.Tyr14396His	missense_variant	83/88			A2

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 712 AN: 151646 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00845

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.00460 AC: 1147 AN: 249298 Hom.: 5 AF XY: 0.00478 AC XY: 647 AN XY: 135246

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00798

Gnomad NFE exome AF: 0.00740

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00739 AC: 10802 AN: 1461506 Hom.: 52 Cov.: 32 AF XY: 0.00724 AC XY: 5265 AN XY: 727060

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.00895

Gnomad4 NFE exome AF: 0.00881

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.00469 AC: 712 AN: 151764 Hom.: 3 Cov.: 32 AF XY: 0.00453 AC XY: 336 AN XY: 74164

Gnomad4 AFR AF: 0.00145

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00845

Gnomad4 NFE AF: 0.00783

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.00648 Hom.: 1

Bravo AF: 0.00394

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00150 AC: 6

ESP6500EA AF: 0.00683 AC: 57

ExAC AF: 0.00456 AC: 551

EpiCase AF: 0.00747

EpiControl AF: 0.00628

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

MUC16: BS2 -

MUC16-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.32
MVP		0.37
ClinPred		0.066	T
GERP RS		4.3
gMVP		0.70

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: rs62118938; hg19: chr19-8969344;