19-8851267-C-G

Position:

• chr19-8851267-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001414686.1(MUC16):​c.44073+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,602,198 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (88 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (73 hom.)
• Consequence: MUC16 NM_001414686.1 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.212

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-8851267-C-G is Benign according to our data. Variant chr19-8851267-C-G is described in ClinVar as [Benign]. Clinvar id is 3044590.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC16	NM_001414686.1	c.44073+9G>C		intron_variant			NP_001401615.1
MUC16	NM_001401501.2	c.43647+9G>C		intron_variant			NP_001388430.1
MUC16	NM_001414687.1	c.43527+9G>C		intron_variant			NP_001401616.1
MUC16	NM_024690.2	c.43425+9G>C		intron_variant			NP_078966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC16	ENST00000710609.1	c.43545+9G>C		intron_variant				ENSP00000518375.1
MUC16	ENST00000397910.8	c.43425+9G>C		intron_variant		5		ENSP00000381008.2
MUC16	ENST00000710610.1	c.34251+9G>C		intron_variant				ENSP00000518376.1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2798 AN: 152134 Hom.: 87 Cov.: 33

Gnomad AFR AF: 0.0648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00450 AC: 1067 AN: 237294 Hom.: 25 AF XY: 0.00343 AC XY: 442 AN XY: 128854

Gnomad AFR exome AF: 0.0625

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000141

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.00182 AC: 2641 AN: 1449946 Hom.: 73 Cov.: 29 AF XY: 0.00160 AC XY: 1152 AN XY: 721124

Gnomad4 AFR exome AF: 0.0675

Gnomad4 AMR exome AF: 0.00294

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000476

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000596

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.0185 AC: 2811 AN: 152252 Hom.: 88 Cov.: 33 AF XY: 0.0178 AC XY: 1325 AN XY: 74426

Gnomad4 AFR AF: 0.0650

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00527 Hom.: 7

Bravo AF: 0.0205

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MUC16-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 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
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80322456; hg19: chr19-8961943;