19-8863312-C-T

Variant names:

• chr19-8863312-C-T
• rs61745929
• NM_001401501.2:c.42905G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The NM_001401501.2(MUC16):​c.42905G>A​(p.Arg14302Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,605,806 control chromosomes in the GnomAD database, including 15 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.138
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004735619).
• BP6: Variant 19-8863312-C-T is Benign according to our data. Variant chr19-8863312-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2649216.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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.42905G>A	p.Arg14302Lys	missense	Exon 85 of 93	NP_001388430.1	A0AAG2UXK0
	MUC16	NM_001414686.1		c.43331G>A	p.Arg14444Lys	missense	Exon 86 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.42785G>A	p.Arg14262Lys	missense	Exon 82 of 90	NP_001401616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.42683G>A	p.Arg14228Lys	missense	Exon 76 of 84	ENSP00000381008.2	Q8WXI7
	MUC16	ENST00000711672.1		c.42869G>A	p.Arg14290Lys	missense	Exon 80 of 88	ENSP00000518832.1	A0AAA9YHI4
	MUC16	ENST00000710609.1		c.42803G>A	p.Arg14268Lys	missense	Exon 79 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152084 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00320 AC: 753 AN: 235578 AF XY: 0.00300

Gnomad AFR exome AF: 0.000698

Gnomad AMR exome AF: 0.000275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.00326 AC: 4732 AN: 1453604 Hom.: 12 Cov.: 32 AF XY: 0.00310 AC XY: 2236 AN XY: 721990

African (AFR) AF: 0.000390 AC: 13 AN: 33376

American (AMR) AF: 0.000208 AC: 9 AN: 43356

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 84264

European-Finnish (FIN) AF: 0.0151 AC: 799 AN: 53038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00342 AC: 3786 AN: 1108270

Other (OTH) AF: 0.00206 AC: 124 AN: 60140

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152202 Hom.: 3 Cov.: 32 AF XY: 0.00335 AC XY: 249 AN XY: 74410

African (AFR) AF: 0.000626 AC: 26 AN: 41528

American (AMR) AF: 0.000393 AC: 6 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0166 AC: 176 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00347 AC: 236 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00279 Hom.: 4

Bravo AF: 0.00174

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000503 AC: 2

ESP6500EA AF: 0.00385 AC: 32

ExAC AF: 0.00322 AC: 389

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	MUC16-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.2
DANN	Benign	0.96
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.14
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.039
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Vest4		0.091
MVP		0.25
ClinPred		0.015	T
GERP RS		2.4
gMVP		0.15
Mutation Taster		=100/0	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: rs61745929; hg19: chr19-8973988;