chr19-8851713-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001401501.2(MUC16):​c.43532C>T​(p.Ser14511Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0388 in 1,462,842 control chromosomes in the GnomAD database, including 1,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.027 (71 hom., cov: 30)
  • Exomes 𝑓: 0.040 (1165 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.06
• Publications: 10 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039216876).
• BP6: Variant 19-8851713-G-A is Benign according to our data. Variant chr19-8851713-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056717.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0273 (4054/148482) while in subpopulation NFE AF = 0.0437 (2931/67058). AF 95% confidence interval is 0.0424. There are 71 homozygotes in GnomAd4. There are 1897 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 71 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	NM_001401501.2	MANE Select	c.43532C>T	p.Ser14511Phe	missense	Exon 91 of 93	NP_001388430.1	A0AAG2UXK0
	MUC16	NM_001414686.1		c.43958C>T	p.Ser14653Phe	missense	Exon 92 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.43412C>T	p.Ser14471Phe	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>T	p.Ser14437Phe	missense	Exon 82 of 84	ENSP00000381008.2	Q8WXI7
	MUC16	ENST00000711672.1		c.43496C>T	p.Ser14499Phe	missense	Exon 86 of 88	ENSP00000518832.1	A0AAA9YHI4
	MUC16	ENST00000710609.1		c.43430C>T	p.Ser14477Phe	missense	Exon 85 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4055 AN: 148424 Hom.: 72 Cov.: 30

Gnomad AFR AF: 0.00766

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.00877

Gnomad EAS AF: 0.000205

Gnomad SAS AF: 0.00345

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0437

Gnomad OTH AF: 0.0274

GnomAD2 exomes AF: 0.0254 AC: 3968 AN: 156192 AF XY: 0.0249

Gnomad AFR exome AF: 0.00654

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00137

Gnomad FIN exome AF: 0.0375

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0401 AC: 52671 AN: 1314360 Hom.: 1165 Cov.: 35 AF XY: 0.0392 AC XY: 25492 AN XY: 649902

African (AFR) AF: 0.00591 AC: 178 AN: 30110

American (AMR) AF: 0.0200 AC: 691 AN: 34618

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 267 AN: 23426

East Asian (EAS) AF: 0.00115 AC: 37 AN: 32048

South Asian (SAS) AF: 0.00363 AC: 283 AN: 77974

European-Finnish (FIN) AF: 0.0434 AC: 1984 AN: 45664

Middle Eastern (MID) AF: 0.00580 AC: 29 AN: 5004

European-Non Finnish (NFE) AF: 0.0469 AC: 47396 AN: 1011376

Other (OTH) AF: 0.0334 AC: 1806 AN: 54140

GnomAD4 genome AF: 0.0273 AC: 4054 AN: 148482 Hom.: 71 Cov.: 30 AF XY: 0.0263 AC XY: 1897 AN XY: 72070

African (AFR) AF: 0.00764 AC: 312 AN: 40842

American (AMR) AF: 0.0239 AC: 356 AN: 14918

Ashkenazi Jewish (ASJ) AF: 0.00877 AC: 30 AN: 3420

East Asian (EAS) AF: 0.000206 AC: 1 AN: 4860

South Asian (SAS) AF: 0.00346 AC: 16 AN: 4630

European-Finnish (FIN) AF: 0.0370 AC: 352 AN: 9520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0437 AC: 2931 AN: 67058

Other (OTH) AF: 0.0272 AC: 56 AN: 2060

Alfa AF: 0.0366 Hom.: 357

Bravo AF: 0.0252

TwinsUK AF: 0.0402 AC: 149

ALSPAC AF: 0.0467 AC: 180

ESP6500AA AF: 0.00990 AC: 35

ESP6500EA AF: 0.0352 AC: 275

ExAC AF: 0.0120 AC: 953

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	MUC16-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.74	T
PhyloP100		4.1
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Vest4		0.11
ClinPred		0.030	T
GERP RS		3.8
gMVP		0.74
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;