rs1862458

Positions:

• chr19-8959116-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001414686.1(MUC16):​c.18200C>T​(p.Ser6067Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,613,506 control chromosomes in the GnomAD database, including 29,491 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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: 𝑓 0.17 (2497 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26994 hom.)
• Consequence: MUC16 NM_001414686.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.282

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056120157).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC16	NM_001414686.1	c.18200C>T	p.Ser6067Phe	missense_variant	7/94		NP_001401615.1
MUC16	NM_001401501.2	c.17774C>T	p.Ser5925Phe	missense_variant	6/93		NP_001388430.1
MUC16	NM_001414687.1	c.17654C>T	p.Ser5885Phe	missense_variant	3/90		NP_001401616.1
MUC16	NM_024690.2	c.17654C>T	p.Ser5885Phe	missense_variant	3/84		NP_078966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC16	ENST00000710609.1	c.17774C>T	p.Ser5925Phe	missense_variant	6/87			ENSP00000518375.1
MUC16	ENST00000397910.8	c.17654C>T	p.Ser5885Phe	missense_variant	3/84	5		ENSP00000381008.2
MUC16	ENST00000710610.1	c.8480C>T	p.Ser2827Phe	missense_variant	5/86			ENSP00000518376.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26413 AN: 151924 Hom.: 2489 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.204 AC: 50766 AN: 248882 Hom.: 5739 AF XY: 0.198 AC XY: 26754 AN XY: 135002

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.302

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.187 AC: 273782 AN: 1461464 Hom.: 26994 Cov.: 65 AF XY: 0.187 AC XY: 136049 AN XY: 727010

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.174 AC: 26428 AN: 152042 Hom.: 2497 Cov.: 32 AF XY: 0.179 AC XY: 13304 AN XY: 74284

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.171

Alfa AF: 0.180 Hom.: 6320

Bravo AF: 0.177

TwinsUK AF: 0.173 AC: 641

ALSPAC AF: 0.167 AC: 645

ESP6500AA AF: 0.102 AC: 403

ESP6500EA AF: 0.182 AC: 1510

ExAC AF: 0.198 AC: 23887

Asia WGS AF: 0.221 AC: 768 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.9
DANN	Benign	0.47
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.023
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.036
ClinPred		0.021	T
GERP RS		1.9
gMVP		0.017

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

Other links and lift over

dbSNP: rs1862458; hg19: chr19-9069792;