19-8851713-G-T

Variant names:

• chr19-8851713-G-T
• rs72999925
• NM_001401501.2:c.43532C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001401501.2(MUC16):​c.43532C>A​(p.Ser14511Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000076 in 1,315,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14511F) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32288986).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001401501.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	NM_001401501.2	MANE Select	c.43532C>A	p.Ser14511Tyr	missense	Exon 91 of 93	NP_001388430.1	A0AAG2UXK0
	MUC16	NM_001414686.1		c.43958C>A	p.Ser14653Tyr	missense	Exon 92 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.43412C>A	p.Ser14471Tyr	missense	Exon 88 of 90	NP_001401616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.43310C>A	p.Ser14437Tyr	missense	Exon 82 of 84	ENSP00000381008.2	Q8WXI7
	MUC16	ENST00000711672.1		c.43496C>A	p.Ser14499Tyr	missense	Exon 86 of 88	ENSP00000518832.1	A0AAA9YHI4
	MUC16	ENST00000710609.1		c.43430C>A	p.Ser14477Tyr	missense	Exon 85 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.60e-7 AC: 1 AN: 1315040 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 650178

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30112

American (AMR) AF: 0.00 AC: 0 AN: 34624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23428

East Asian (EAS) AF: 0.00 AC: 0 AN: 32048

South Asian (SAS) AF: 0.00 AC: 0 AN: 77974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5006

European-Non Finnish (NFE) AF: 9.88e-7 AC: 1 AN: 1012028

Other (OTH) AF: 0.00 AC: 0 AN: 54152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.54	T
PhyloP100		4.1
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Vest4		0.24
MVP		0.46
ClinPred		0.91	D
GERP RS		3.8
gMVP		0.73
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs72999925; hg19: chr19-8962389;