dbSNP rs78717907: MUC16:p.His14237Gln (chr19-8871536-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001414686.1(MUC16):c.42711T>G(p.His14237Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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: 31)

Consequence

MUC16
NM_001414686.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -8.12

Variant links:

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]

MUC16 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06661433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
MUC16	NM_001414686.1 link	c.42711T>G	p.His14237Gln	missense_variant	Exon 80 of 94	NP_001401615.1
MUC16	NM_001401501.2 link	c.42285T>G	p.His14095Gln	missense_variant	Exon 79 of 93	NP_001388430.1
MUC16	NM_001414687.1 link	c.42165T>G	p.His14055Gln	missense_variant	Exon 76 of 90	NP_001401616.1
MUC16	NM_024690.2 link	c.42063T>G	p.His14021Gln	missense_variant	Exon 70 of 84	NP_078966.2	Q8WXI7B3KY81

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
MUC16	ENST00000710609.1 link	c.42183T>G	p.His14061Gln	missense_variant	Exon 73 of 87		ENSP00000518375.1
MUC16	ENST00000397910.8 link	c.42063T>G	p.His14021Gln	missense_variant	Exon 70 of 84	5	ENSP00000381008.2	Q8WXI7
MUC16	ENST00000710610.1 link	c.32889T>G	p.His10963Gln	missense_variant	Exon 72 of 86		ENSP00000518376.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000414

AC:

AN:

241286

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000911

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.0020

DANN

Benign

0.75

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.12

M_CAP

Benign

0.016

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.88

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.13

Sift

Benign

0.058

Sift4G

Benign

0.079

Vest4

0.077

MVP

0.040

ClinPred

0.092

GERP RS

-7.8

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over