19-8858760-A-T

Position:

• chr19-8858760-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_001414686.1(MUC16):​c.43565-9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,510,964 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0051 (30 hom.)
• Consequence: MUC16 NM_001414686.1 intron
• Scores: Splicing: ADA: 0.001623
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.210

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-8858760-A-T is Benign according to our data. Variant chr19-8858760-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3037390.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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	Protein	UniProt
MUC16	NM_001414686.1	c.43565-9T>A		intron_variant			NP_001401615.1
MUC16	NM_001401501.2	c.43139-9T>A		intron_variant			NP_001388430.1
MUC16	NM_001414687.1	c.43019-9T>A		intron_variant			NP_001401616.1
MUC16	NM_024690.2	c.42917-9T>A		intron_variant			NP_078966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC16	ENST00000710609.1	c.43037-9T>A		intron_variant				ENSP00000518375.1
MUC16	ENST00000397910.8	c.42917-9T>A		intron_variant		5		ENSP00000381008.2
MUC16	ENST00000710610.1	c.33743-9T>A		intron_variant				ENSP00000518376.1

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 503 AN: 151268 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000825

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00430

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.000862

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00558

Gnomad OTH AF: 0.00386

GnomAD3 exomes AF: 0.00350 AC: 769 AN: 219568 Hom.: 3 AF XY: 0.00329 AC XY: 393 AN XY: 119518

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.000225

Gnomad EAS exome AF: 0.0000645

Gnomad SAS exome AF: 0.000761

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.00649

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.00514 AC: 6990 AN: 1359574 Hom.: 30 Cov.: 31 AF XY: 0.00507 AC XY: 3433 AN XY: 677382

Gnomad4 AFR exome AF: 0.000971

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.000123

Gnomad4 EAS exome AF: 0.0000802

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00616

Gnomad4 OTH exome AF: 0.00645

GnomAD4 genome AF: 0.00332 AC: 503 AN: 151390 Hom.: 2 Cov.: 31 AF XY: 0.00304 AC XY: 225 AN XY: 73912

Gnomad4 AFR AF: 0.000823

Gnomad4 AMR AF: 0.00429

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.000862

Gnomad4 NFE AF: 0.00558

Gnomad4 OTH AF: 0.00382

Alfa AF: 0.00413 Hom.: 0

Bravo AF: 0.00368

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MUC16-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.091
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.072
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: rs75741349; hg19: chr19-8969436;