19-8871641-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001414686.1(MUC16):c.42606C>T(p.Asn14202=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,568,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: MUC16 NM_001414686.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.21

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-8871641-G-A is Benign according to our data. Variant chr19-8871641-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2649218.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.21 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC16	NM_001401501.2	c.42180C>T	p.Asn14060=	synonymous_variant	79/93	ENST00000711671.1
MUC16	NM_001414686.1	c.42606C>T	p.Asn14202=	synonymous_variant	80/94
MUC16	NM_001414687.1	c.42060C>T	p.Asn14020=	synonymous_variant	76/90
MUC16	NM_024690.2	c.41958C>T	p.Asn13986=	synonymous_variant	70/84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC16	ENST00000711672.1	c.42144C>T	p.Asn14048=	synonymous_variant	74/88			A2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152058 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000106 AC: 22 AN: 208214 Hom.: 0 AF XY: 0.000115 AC XY: 13 AN XY: 112594

Gnomad AFR exome AF: 0.000568

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000131

Gnomad SAS exome AF: 0.0000428

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.000133 AC: 189 AN: 1415896 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 94 AN XY: 702022

Gnomad4 AFR exome AF: 0.000469

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000800

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.0000686

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152176 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74396

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000305 Hom.: 0

Bravo AF: 0.000170

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

MUC16: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.040
Dann	Benign	0.32

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: rs372141764; hg19: chr19-8982317;