rs2591592

Variant names:

• chr19-8964670-T-A
• rs2591592
• NM_001401501.2:c.12220A>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.12220A>T​(p.Ile4074Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,613,456 control chromosomes in the GnomAD database, including 257,726 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.51 (20447 hom., cov: 31)
  • Exomes 𝑓: 0.56 (237279 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.774
• Publications: 34 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=3.0184352E-5).
• BP6: Variant 19-8964670-T-A is Benign according to our data. Variant chr19-8964670-T-A is described in ClinVar as Benign. ClinVar VariationId is 3059888.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.579 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.12220A>T	p.Ile4074Phe	missense	Exon 6 of 93	NP_001388430.1
	MUC16	NM_001414686.1		c.12646A>T	p.Ile4216Phe	missense	Exon 7 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.12100A>T	p.Ile4034Phe	missense	Exon 3 of 90	NP_001401616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.12100A>T	p.Ile4034Phe	missense	Exon 3 of 84	ENSP00000381008.2
	MUC16	ENST00000711672.1		c.12220A>T	p.Ile4074Phe	missense	Exon 6 of 88	ENSP00000518832.1
	MUC16	ENST00000710609.1		c.12220A>T	p.Ile4074Phe	missense	Exon 6 of 87	ENSP00000518375.1

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77670 AN: 151844 Hom.: 20436 Cov.: 31

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.530

GnomAD2 exomes AF: 0.514 AC: 128058 AN: 248968 AF XY: 0.524

Gnomad AFR exome AF: 0.411

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.572

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.535

GnomAD4 exome AF: 0.565 AC: 825171 AN: 1461494 Hom.: 237279 Cov.: 62 AF XY: 0.565 AC XY: 410413 AN XY: 727024

African (AFR) AF: 0.404 AC: 13511 AN: 33476

American (AMR) AF: 0.445 AC: 19917 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 14983 AN: 26130

East Asian (EAS) AF: 0.247 AC: 9793 AN: 39694

South Asian (SAS) AF: 0.539 AC: 46466 AN: 86252

European-Finnish (FIN) AF: 0.495 AC: 26454 AN: 53400

Middle Eastern (MID) AF: 0.539 AC: 3107 AN: 5766

European-Non Finnish (NFE) AF: 0.592 AC: 657714 AN: 1111698

Other (OTH) AF: 0.550 AC: 33226 AN: 60366

GnomAD4 genome AF: 0.511 AC: 77711 AN: 151962 Hom.: 20447 Cov.: 31 AF XY: 0.506 AC XY: 37600 AN XY: 74264

African (AFR) AF: 0.418 AC: 17314 AN: 41430

American (AMR) AF: 0.516 AC: 7865 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1986 AN: 3472

East Asian (EAS) AF: 0.272 AC: 1405 AN: 5170

South Asian (SAS) AF: 0.502 AC: 2418 AN: 4814

European-Finnish (FIN) AF: 0.489 AC: 5163 AN: 10564

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.583 AC: 39646 AN: 67952

Other (OTH) AF: 0.524 AC: 1105 AN: 2108

Alfa AF: 0.564 Hom.: 7866

Bravo AF: 0.507

TwinsUK AF: 0.611 AC: 2266

ALSPAC AF: 0.599 AC: 2308

ESP6500AA AF: 0.448 AC: 1807

ESP6500EA AF: 0.592 AC: 4917

ExAC AF: 0.515 AC: 62229

Asia WGS AF: 0.386 AC: 1343 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	0.10
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.28
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.000030	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.77
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.023
Sift	Benign	0.75	T
Sift4G	Uncertain	0.025	D
Vest4		0.032
ClinPred		0.013	T
GERP RS		-1.1
gMVP		0.036
Mutation Taster		=99/1	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: rs2591592; hg19: chr19-9075346; COSMIC: COSV67453691;