19-8969786-C-T

Variant names:

• chr19-8969786-C-T
• rs2547065
• NM_001401501.2:c.9689G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001401501.2(MUC16):​c.9689G>A​(p.Ser3230Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. S3230T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 31 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07712683).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	NM_001401501.2	MANE Select	c.9689G>A	p.Ser3230Asn	missense	Exon 5 of 93	NP_001388430.1
	MUC16	NM_001414686.1		c.10115G>A	p.Ser3372Asn	missense	Exon 6 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.9569G>A	p.Ser3190Asn	missense	Exon 2 of 90	NP_001401616.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.9569G>A	p.Ser3190Asn	missense	Exon 2 of 84	ENSP00000381008.2
	MUC16	ENST00000711672.1		c.9689G>A	p.Ser3230Asn	missense	Exon 5 of 88	ENSP00000518832.1
	MUC16	ENST00000710609.1		c.9689G>A	p.Ser3230Asn	missense	Exon 5 of 87	ENSP00000518375.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446318 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720414

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1098106

Other (OTH) AF: 0.00 AC: 0 AN: 59872

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.3
DANN	Benign	0.48
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.19
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.034
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0090	D
Vest4		0.066
MutPred		0.15		Loss of glycosylation at S3190 (P = 0.0032)
MVP		0.030
ClinPred		0.053	T
GERP RS		0.93
gMVP		0.037
Mutation Taster		=99/1	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: rs2547065; hg19: chr19-9080462;