rs2547065

Variant names:

• chr19-8969786-C-G
• rs2547065
• NM_001401501.2:c.9689G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-8969786-C-G
• chr19-8969786-C-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.9689G>C​(p.Ser3230Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,596,140 control chromosomes in the GnomAD database, including 302,149 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 0.57 (25076 hom., cov: 30)
  • Exomes 𝑓: 0.62 (277073 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.189
• Publications: 31 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=4.1319427E-6).
• BP6: Variant 19-8969786-C-G is Benign according to our data. Variant chr19-8969786-C-G is described in ClinVar as Benign. ClinVar VariationId is 3059043.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC16	NM_001401501.2	c.9689G>C	p.Ser3230Thr	missense_variant	Exon 5 of 93	ENST00000711671.1	NP_001388430.1
MUC16	NM_001414686.1	c.10115G>C	p.Ser3372Thr	missense_variant	Exon 6 of 94		NP_001401615.1
MUC16	NM_001414687.1	c.9569G>C	p.Ser3190Thr	missense_variant	Exon 2 of 90		NP_001401616.1
MUC16	NM_024690.2	c.9569G>C	p.Ser3190Thr	missense_variant	Exon 2 of 84		NP_078966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC16	ENST00000397910.8	c.9569G>C	p.Ser3190Thr	missense_variant	Exon 2 of 84	5		ENSP00000381008.2
MUC16	ENST00000711672.1	c.9689G>C	p.Ser3230Thr	missense_variant	Exon 5 of 88			ENSP00000518832.1
MUC16	ENST00000710609.1	c.9689G>C	p.Ser3230Thr	missense_variant	Exon 5 of 87			ENSP00000518375.1
MUC16	ENST00000710610.1	c.395G>C	p.Ser132Thr	missense_variant	Exon 4 of 86			ENSP00000518376.1

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86307 AN: 151742 Hom.: 25051 Cov.: 30

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.570

GnomAD2 exomes AF: 0.607 AC: 150122 AN: 247456 AF XY: 0.605

Gnomad AFR exome AF: 0.446

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.542

Gnomad EAS exome AF: 0.816

Gnomad FIN exome AF: 0.562

Gnomad NFE exome AF: 0.597

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.615 AC: 888858 AN: 1444280 Hom.: 277073 Cov.: 30 AF XY: 0.614 AC XY: 441806 AN XY: 719478

African (AFR) AF: 0.455 AC: 15008 AN: 33012

American (AMR) AF: 0.652 AC: 29103 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 14047 AN: 26016

East Asian (EAS) AF: 0.838 AC: 33178 AN: 39596

South Asian (SAS) AF: 0.603 AC: 51726 AN: 85818

European-Finnish (FIN) AF: 0.560 AC: 29886 AN: 53358

Middle Eastern (MID) AF: 0.460 AC: 2636 AN: 5734

European-Non Finnish (NFE) AF: 0.617 AC: 676951 AN: 1096286

Other (OTH) AF: 0.607 AC: 36323 AN: 59814

GnomAD4 genome AF: 0.569 AC: 86371 AN: 151860 Hom.: 25076 Cov.: 30 AF XY: 0.569 AC XY: 42247 AN XY: 74192

African (AFR) AF: 0.461 AC: 19104 AN: 41408

American (AMR) AF: 0.628 AC: 9596 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1872 AN: 3468

East Asian (EAS) AF: 0.823 AC: 4236 AN: 5146

South Asian (SAS) AF: 0.627 AC: 3018 AN: 4812

European-Finnish (FIN) AF: 0.558 AC: 5875 AN: 10530

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.600 AC: 40755 AN: 67914

Other (OTH) AF: 0.571 AC: 1204 AN: 2108

Alfa AF: 0.598 Hom.: 20605

Bravo AF: 0.572

TwinsUK AF: 0.621 AC: 2302

ALSPAC AF: 0.619 AC: 2387

ESP6500AA AF: 0.475 AC: 1826

ESP6500EA AF: 0.610 AC: 5021

ExAC AF: 0.599 AC: 72407

Asia WGS AF: 0.706 AC: 2453 AN: 3474

EpiCase AF: 0.588

EpiControl AF: 0.587

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MUC16-related disorder Benign:1

Oct 17, 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	0.046
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.20
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.000030	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000041	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.19
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	0.83	T
Vest4		0.024
ClinPred		0.000016	T
GERP RS		0.93
gMVP		0.063
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: rs2547065; hg19: chr19-9080462; COSMIC: COSV107513262;