19-8863312-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001414686.1(MUC16):c.43331G>A(p.Arg14444Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,605,806 control chromosomes in the GnomAD database, including 15 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.138

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004735619).
• BP6: Variant 19-8863312-C-T is Benign according to our data. Variant chr19-8863312-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2649216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.42905G>A	p.Arg14302Lys	missense_variant	85/93	ENST00000711671.1
MUC16	NM_001414686.1	c.43331G>A	p.Arg14444Lys	missense_variant	86/94
MUC16	NM_001414687.1	c.42785G>A	p.Arg14262Lys	missense_variant	82/90
MUC16	NM_024690.2	c.42683G>A	p.Arg14228Lys	missense_variant	76/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42869G>A	p.Arg14290Lys	missense_variant	80/88			A2

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152084 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00320 AC: 753 AN: 235578 Hom.: 3 AF XY: 0.00300 AC XY: 381 AN XY: 127182

Gnomad AFR exome AF: 0.000698

Gnomad AMR exome AF: 0.000275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.00326 AC: 4732 AN: 1453604 Hom.: 12 Cov.: 32 AF XY: 0.00310 AC XY: 2236 AN XY: 721990

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.000208

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.00342

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152202 Hom.: 3 Cov.: 32 AF XY: 0.00335 AC XY: 249 AN XY: 74410

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.00347

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00296 Hom.: 3

Bravo AF: 0.00174

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000503 AC: 2

ESP6500EA AF: 0.00385 AC: 32

ExAC AF: 0.00322 AC: 389

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Nov 01, 2022

MUC16: BP4, BS2 -

MUC16-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 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	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	9.2
Dann	Benign	0.96
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.039
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Vest4		0.091
MVP		0.25
ClinPred		0.015	T
GERP RS		2.4
gMVP		0.15

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: rs61745929; hg19: chr19-8973988;