rs2547068

Variant names:

• chr19-8964541-T-A
• rs2547068
• ENST00000397910.8:c.12229A>T

Variant summary

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

The ENST00000397910.8(MUC16):​c.12229A>T​(p.Thr4077Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,613,642 control chromosomes in the GnomAD database, including 68,895 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 0.26 (5118 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63777 hom.)
• Consequence: MUC16 ENST00000397910.8 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.833
• Publications: 20 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=0.0038928986).
• BP6: Variant 19-8964541-T-A is Benign according to our data. Variant chr19-8964541-T-A is described in ClinVar as Benign. ClinVar VariationId is 3060874.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC16	NM_001414686.1	c.12775A>T	p.Thr4259Ser	missense_variant	Exon 7 of 94		NP_001401615.1
MUC16	NM_001401501.2	c.12349A>T	p.Thr4117Ser	missense_variant	Exon 6 of 93		NP_001388430.1
MUC16	NM_001414687.1	c.12229A>T	p.Thr4077Ser	missense_variant	Exon 3 of 90		NP_001401616.1
MUC16	NM_024690.2	c.12229A>T	p.Thr4077Ser	missense_variant	Exon 3 of 84		NP_078966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC16	ENST00000397910.8	c.12229A>T	p.Thr4077Ser	missense_variant	Exon 3 of 84	5		ENSP00000381008.2
MUC16	ENST00000711672.1	c.12349A>T	p.Thr4117Ser	missense_variant	Exon 6 of 88			ENSP00000518832.1
MUC16	ENST00000710609.1	c.12349A>T	p.Thr4117Ser	missense_variant	Exon 6 of 87			ENSP00000518375.1
MUC16	ENST00000710610.1	c.3055A>T	p.Thr1019Ser	missense_variant	Exon 5 of 86			ENSP00000518376.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39002 AN: 151972 Hom.: 5112 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.262 AC: 65287 AN: 248770 AF XY: 0.267

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.291

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.292 AC: 426712 AN: 1461552 Hom.: 63777 Cov.: 68 AF XY: 0.291 AC XY: 211872 AN XY: 727058

African (AFR) AF: 0.199 AC: 6661 AN: 33476

American (AMR) AF: 0.224 AC: 10003 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4511 AN: 26130

East Asian (EAS) AF: 0.240 AC: 9543 AN: 39690

South Asian (SAS) AF: 0.283 AC: 24429 AN: 86254

European-Finnish (FIN) AF: 0.237 AC: 12635 AN: 53394

Middle Eastern (MID) AF: 0.167 AC: 962 AN: 5764

European-Non Finnish (NFE) AF: 0.307 AC: 341057 AN: 1111764

Other (OTH) AF: 0.280 AC: 16911 AN: 60364

GnomAD4 genome AF: 0.257 AC: 39034 AN: 152090 Hom.: 5118 Cov.: 32 AF XY: 0.253 AC XY: 18811 AN XY: 74344

African (AFR) AF: 0.201 AC: 8343 AN: 41514

American (AMR) AF: 0.269 AC: 4102 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 624 AN: 3468

East Asian (EAS) AF: 0.265 AC: 1367 AN: 5162

South Asian (SAS) AF: 0.274 AC: 1321 AN: 4820

European-Finnish (FIN) AF: 0.239 AC: 2528 AN: 10588

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.292 AC: 19870 AN: 67962

Other (OTH) AF: 0.259 AC: 545 AN: 2106

Alfa AF: 0.267 Hom.: 1870

Bravo AF: 0.258

TwinsUK AF: 0.316 AC: 1171

ALSPAC AF: 0.322 AC: 1242

ESP6500AA AF: 0.197 AC: 773

ESP6500EA AF: 0.289 AC: 2394

ExAC AF: 0.262 AC: 31615

Asia WGS AF: 0.259 AC: 901 AN: 3474

EpiCase AF: 0.286

EpiControl AF: 0.288

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MUC16-related disorder Benign:1

Oct 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.5
DANN	Benign	0.30
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.91	T
PhyloP100		-0.83
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.034
Sift	Benign	0.080	T
Sift4G	Uncertain	0.021	D
Vest4		0.012
MutPred		0.12		Gain of phosphorylation at T4077 (P = 0.0688);
ClinPred		0.0056	T
GERP RS		-0.16
gMVP		0.053
Mutation Taster		=100/0	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: rs2547068; hg19: chr19-9075217; COSMIC: COSV67453685;