chr19-8862883-T-C

Variant names:

• chr19-8862883-T-C
• rs61734967
• NM_001401501.2:c.42979A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001401501.2(MUC16):​c.42979A>G​(p.Thr14327Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,604,718 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0054 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (7 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.39
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069482327).
• BP6: Variant 19-8862883-T-C is Benign according to our data. Variant chr19-8862883-T-C is described in ClinVar as Benign. ClinVar VariationId is 3033479.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00543 (827/152232) while in subpopulation AFR AF = 0.0165 (687/41526). AF 95% confidence interval is 0.0155. There are 10 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.42979A>G	p.Thr14327Ala	missense	Exon 86 of 93	NP_001388430.1	A0AAG2UXK0
	MUC16	NM_001414686.1		c.43405A>G	p.Thr14469Ala	missense	Exon 87 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.42859A>G	p.Thr14287Ala	missense	Exon 83 of 90	NP_001401616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.42757A>G	p.Thr14253Ala	missense	Exon 77 of 84	ENSP00000381008.2	Q8WXI7
	MUC16	ENST00000711672.1		c.42943A>G	p.Thr14315Ala	missense	Exon 81 of 88	ENSP00000518832.1	A0AAA9YHI4
	MUC16	ENST00000710609.1		c.42877A>G	p.Thr14293Ala	missense	Exon 80 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 821 AN: 152114 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00240 AC: 563 AN: 234794 AF XY: 0.00227

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00869

Gnomad FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.000226

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000982 AC: 1427 AN: 1452486 Hom.: 7 Cov.: 31 AF XY: 0.00104 AC XY: 753 AN XY: 721378

African (AFR) AF: 0.0150 AC: 502 AN: 33386

American (AMR) AF: 0.00120 AC: 52 AN: 43258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00950 AC: 375 AN: 39472

South Asian (SAS) AF: 0.00363 AC: 305 AN: 83930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52936

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5756

European-Non Finnish (NFE) AF: 0.0000912 AC: 101 AN: 1107708

Other (OTH) AF: 0.00145 AC: 87 AN: 60138

GnomAD4 genome AF: 0.00543 AC: 827 AN: 152232 Hom.: 10 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74418

African (AFR) AF: 0.0165 AC: 687 AN: 41526

American (AMR) AF: 0.00164 AC: 25 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5170

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68014

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00195 Hom.: 3

Bravo AF: 0.00549

ESP6500AA AF: 0.0123 AC: 50

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.00257 AC: 311

Asia WGS AF: 0.00866 AC: 30 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	0.20
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.75	T
PhyloP100		1.4
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.095
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Vest4		0.13
MVP		0.23
ClinPred		0.031	T
GERP RS		4.4
gMVP		0.24
Mutation Taster		=99/1	polymorphism

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: rs61734967; hg19: chr19-8973559;