19-8977341-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001414686.1(MUC16):c.4344A>C(p.Lys1448Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,708 control chromosomes in the GnomAD database, including 408,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.77 (46017 hom., cov: 30)
  • Exomes 𝑓: 0.70 (362022 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.32

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=1.4046769E-6).
• BP6: Variant 19-8977341-T-G is Benign according to our data. Variant chr19-8977341-T-G is described in ClinVar as [Benign]. Clinvar id is 3059093.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.3918A>C	p.Lys1306Asn	missense_variant	4/93	ENST00000711671.1
MUC16	NM_001414686.1	c.4344A>C	p.Lys1448Asn	missense_variant	5/94
MUC16	NM_001414687.1	c.3798A>C	p.Lys1266Asn	missense_variant	1/90
MUC16	NM_024690.2	c.3798A>C	p.Lys1266Asn	missense_variant	1/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.3918A>C	p.Lys1306Asn	missense_variant	4/88			A2
MUC16	ENST00000710609.1	c.3918A>C	p.Lys1306Asn	missense_variant	4/87			A2
MUC16	ENST00000397910.8	c.3798A>C	p.Lys1266Asn	missense_variant	1/84	5		P2
MUC16	ENST00000710610.1	c.302-7462A>C		intron_variant				A2

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117356 AN: 151918 Hom.: 45951 Cov.: 30

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.807

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.763

GnomAD3 exomes AF: 0.743 AC: 185321 AN: 249274 Hom.: 69581 AF XY: 0.739 AC XY: 99888 AN XY: 135224

Gnomad AFR exome AF: 0.924

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.804

Gnomad EAS exome AF: 0.712

Gnomad SAS exome AF: 0.754

Gnomad FIN exome AF: 0.786

Gnomad NFE exome AF: 0.692

Gnomad OTH exome AF: 0.744

GnomAD4 exome AF: 0.701 AC: 1024741 AN: 1461670 Hom.: 362022 Cov.: 68 AF XY: 0.703 AC XY: 511149 AN XY: 727112

Gnomad4 AFR exome AF: 0.931

Gnomad4 AMR exome AF: 0.790

Gnomad4 ASJ exome AF: 0.802

Gnomad4 EAS exome AF: 0.765

Gnomad4 SAS exome AF: 0.756

Gnomad4 FIN exome AF: 0.780

Gnomad4 NFE exome AF: 0.676

Gnomad4 OTH exome AF: 0.723

GnomAD4 genome AF: 0.773 AC: 117484 AN: 152038 Hom.: 46017 Cov.: 30 AF XY: 0.777 AC XY: 57755 AN XY: 74294

Gnomad4 AFR AF: 0.917

Gnomad4 AMR AF: 0.756

Gnomad4 ASJ AF: 0.807

Gnomad4 EAS AF: 0.720

Gnomad4 SAS AF: 0.748

Gnomad4 FIN AF: 0.786

Gnomad4 NFE AF: 0.691

Gnomad4 OTH AF: 0.766

Alfa AF: 0.708 Hom.: 94049

Bravo AF: 0.776

TwinsUK AF: 0.663 AC: 2458

ALSPAC AF: 0.660 AC: 2543

ESP6500AA AF: 0.911 AC: 3844

ESP6500EA AF: 0.699 AC: 5914

ExAC AF: 0.744 AC: 90001

Asia WGS AF: 0.743 AC: 2586 AN: 3478

EpiCase AF: 0.699

EpiControl AF: 0.702

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 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	0.037
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	4.8
Dann	Benign	0.40
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00056	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.022
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Vest4		0.010
ClinPred		0.00045	T
GERP RS		-2.0
gMVP		0.040

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: rs1596797; hg19: chr19-9088017; COSMIC: COSV67441930;