19-8851713-G-T

Variant names:

• chr19-8851713-G-T
• NM_001414686.1:c.43958C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001414686.1(MUC16):​c.43958C>A​(p.Ser14653Tyr) 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.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06

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 Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC16	NM_001414686.1	c.43958C>A	p.Ser14653Tyr	missense_variant	Exon 92 of 94		NP_001401615.1
MUC16	NM_001401501.2	c.43532C>A	p.Ser14511Tyr	missense_variant	Exon 91 of 93		NP_001388430.1
MUC16	NM_001414687.1	c.43412C>A	p.Ser14471Tyr	missense_variant	Exon 88 of 90		NP_001401616.1
MUC16	NM_024690.2	c.43310C>A	p.Ser14437Tyr	missense_variant	Exon 82 of 84		NP_078966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC16	ENST00000710609.1	c.43430C>A	p.Ser14477Tyr	missense_variant	Exon 85 of 87			ENSP00000518375.1
MUC16	ENST00000397910.8	c.43310C>A	p.Ser14437Tyr	missense_variant	Exon 82 of 84	5		ENSP00000381008.2
MUC16	ENST00000710610.1	c.34136C>A	p.Ser11379Tyr	missense_variant	Exon 84 of 86			ENSP00000518376.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.88e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-8962389;