Genetic Variant MUC16:p.Pro14124Ala (chr19-8868547-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001401501.2(MUC16):c.42370C>G(p.Pro14124Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,710 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.017 ( 53 hom., cov: 32)

Exomes 𝑓: 0.016 ( 397 hom. )

Consequence

MUC16
NM_001401501.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.67

Publications

11 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039281845).

BP6

Variant 19-8868547-G-C is Benign according to our data. Variant chr19-8868547-G-C is described in ClinVar as Benign. ClinVar VariationId is 3038195.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0167 (2543/152216) while in subpopulation NFE AF = 0.0207 (1407/67990). AF 95% confidence interval is 0.0198. There are 53 homozygotes in GnomAd4. There are 1389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 53 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC16	NM_001401501.2	MANE Select	c.42370C>G	p.Pro14124Ala	missense	Exon 80 of 93	NP_001388430.1	A0AAG2UXK0
MUC16	NM_001414686.1		c.42796C>G	p.Pro14266Ala	missense	Exon 81 of 94	NP_001401615.1
MUC16	NM_001414687.1		c.42250C>G	p.Pro14084Ala	missense	Exon 77 of 90	NP_001401616.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC16	ENST00000397910.8	TSL:5	c.42148C>G	p.Pro14050Ala	missense	Exon 71 of 84	ENSP00000381008.2	Q8WXI7
MUC16	ENST00000711672.1		c.42334C>G	p.Pro14112Ala	missense	Exon 75 of 88	ENSP00000518832.1	A0AAA9YHI4
MUC16	ENST00000710609.1		c.42268C>G	p.Pro14090Ala	missense	Exon 74 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2545

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0651

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0207

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0194

AC:

4834

AN:

249064

AF XY:

0.0200

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00722

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0624

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0227

GnomAD4 exome

AF:

0.0162

AC:

23678

AN:

1461494

Hom.:

397

Cov.:

AF XY:

0.0168

AC XY:

12243

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33476

American (AMR)

AF:

0.00752

AC:

336

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0274

AC:

716

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0199

AC:

1716

AN:

86230

European-Finnish (FIN)

AF:

0.0594

AC:

3172

AN:

53390

Middle Eastern (MID)

AF:

0.0369

AC:

213

AN:

5766

European-Non Finnish (NFE)

AF:

0.0148

AC:

16478

AN:

1111744

Other (OTH)

AF:

0.0166

AC:

1000

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1181

2362

3542

4723

5904

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

478

956

1434

1912

2390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0167

AC:

2543

AN:

152216

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

1389

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41552

American (AMR)

AF:

0.00889

AC:

136

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0180

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0651

AC:

690

AN:

10594

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0207

AC:

1407

AN:

67990

Other (OTH)

AF:

0.0161

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00255

AC:

ESP6500EA

AF:

0.0162

AC:

134

ExAC

AF:

0.0187

AC:

2256

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0195

EpiControl

AF:

0.0164

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

MUC16-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.1

PhyloP100

1.7

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.12

Sift

Benign

0.062

Sift4G

Uncertain

0.032

Vest4

0.072

ClinPred

0.035

GERP RS

3.2

gMVP

0.19

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over