rs12459358

Variant names:

• chr19-9040354-C-T
• rs12459358
• NM_001414686.1:c.83-4286G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B.

Score: -12 - Benign

-12

BP4_StrongBA1

The NM_001414686.1(MUC16):​c.83-4286G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 151,910 control chromosomes in the GnomAD database, including 9,252 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9252 hom., cov: 30)
• Consequence: MUC16 NM_001414686.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00700
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC16	NM_001414686.1	c.83-4286G>A		intron_variant	Intron 1 of 93		NP_001401615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51310 AN: 151790 Hom.: 9248 Cov.: 30

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.337

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.338 AC: 51343 AN: 151910 Hom.: 9252 Cov.: 30 AF XY: 0.337 AC XY: 25033 AN XY: 74224

African (AFR) AF: 0.222 AC: 9212 AN: 41476

American (AMR) AF: 0.428 AC: 6507 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1143 AN: 3464

East Asian (EAS) AF: 0.212 AC: 1092 AN: 5144

South Asian (SAS) AF: 0.394 AC: 1894 AN: 4802

European-Finnish (FIN) AF: 0.324 AC: 3422 AN: 10552

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26858 AN: 67954

Other (OTH) AF: 0.332 AC: 699 AN: 2104

Alfa AF: 0.367 Hom.: 2102

Bravo AF: 0.340

Asia WGS AF: 0.277 AC: 963 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.0
DANN	Benign	0.89
PhyloP100		-0.0070

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12459358; hg19: chr19-9151030;