rs3752141

Variant names:

• chr19-8871595-G-A
• rs3752141
• NM_001401501.2:c.42226C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001401501.2(MUC16):​c.42226C>T​(p.Leu14076Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00804 in 1,608,972 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (55 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (376 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.443
• Publications: 8 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=0.0025821626).
• BP6: Variant 19-8871595-G-A is Benign according to our data. Variant chr19-8871595-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059793.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

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.42226C>T	p.Leu14076Phe	missense	Exon 79 of 93	NP_001388430.1	A0AAG2UXK0
	MUC16	NM_001414686.1		c.42652C>T	p.Leu14218Phe	missense	Exon 80 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.42106C>T	p.Leu14036Phe	missense	Exon 76 of 90	NP_001401616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.42004C>T	p.Leu14002Phe	missense	Exon 70 of 84	ENSP00000381008.2	Q8WXI7
	MUC16	ENST00000711672.1		c.42190C>T	p.Leu14064Phe	missense	Exon 74 of 88	ENSP00000518832.1	A0AAA9YHI4
	MUC16	ENST00000710609.1		c.42124C>T	p.Leu14042Phe	missense	Exon 73 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1565 AN: 152092 Hom.: 55 Cov.: 31

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.0974

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.0225 AC: 5485 AN: 243608 AF XY: 0.0213

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.0655

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.0967

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000588

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.00780 AC: 11362 AN: 1456762 Hom.: 376 Cov.: 32 AF XY: 0.00875 AC XY: 6342 AN XY: 724610

African (AFR) AF: 0.000811 AC: 27 AN: 33304

American (AMR) AF: 0.0636 AC: 2813 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 142 AN: 25956

East Asian (EAS) AF: 0.0883 AC: 3460 AN: 39178

South Asian (SAS) AF: 0.0467 AC: 3989 AN: 85504

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53270

Middle Eastern (MID) AF: 0.00262 AC: 15 AN: 5736

European-Non Finnish (NFE) AF: 0.000327 AC: 363 AN: 1109410

Other (OTH) AF: 0.00905 AC: 545 AN: 60196

GnomAD4 genome AF: 0.0103 AC: 1569 AN: 152210 Hom.: 55 Cov.: 31 AF XY: 0.0121 AC XY: 900 AN XY: 74424

African (AFR) AF: 0.00130 AC: 54 AN: 41540

American (AMR) AF: 0.0430 AC: 658 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.0970 AC: 500 AN: 5152

South Asian (SAS) AF: 0.0550 AC: 265 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68014

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00627 Hom.: 93

Bravo AF: 0.0137

ESP6500AA AF: 0.00194 AC: 8

ESP6500EA AF: 0.000593 AC: 5

ExAC AF: 0.0217 AC: 2623

Asia WGS AF: 0.0550 AC: 193 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	0.089
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.6
DANN	Uncertain	0.98
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.44
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.062
Sift	Benign	0.48	T
Sift4G	Benign	0.17	T
Vest4		0.032
ClinPred		0.027	T
GERP RS		1.8
gMVP		0.091
Mutation Taster		=98/2	polymorphism (auto)

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: rs3752141; hg19: chr19-8982271; COSMIC: COSV66689691; COSMIC: COSV66689691;