chr19-8871590-G-A

Variant names:

• chr19-8871590-G-A
• rs76124866
• NM_001401501.2:c.42231C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001401501.2(MUC16):​c.42231C>T​(p.Ser14077Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,608,516 control chromosomes in the GnomAD database, including 510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.020 (40 hom., cov: 31)
  • Exomes 𝑓: 0.023 (470 hom.)
• Consequence: MUC16 NM_001401501.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -7.13
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.012).
• BP6: Variant 19-8871590-G-A is Benign according to our data. Variant chr19-8871590-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056085.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-7.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0202 (3072/152178) while in subpopulation NFE AF = 0.024 (1634/67994). AF 95% confidence interval is 0.0231. There are 40 homozygotes in GnomAd4. There are 1443 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

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.42231C>T	p.Ser14077Ser	synonymous	Exon 79 of 93	NP_001388430.1	A0AAG2UXK0
	MUC16	NM_001414686.1		c.42657C>T	p.Ser14219Ser	synonymous	Exon 80 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.42111C>T	p.Ser14037Ser	synonymous	Exon 76 of 90	NP_001401616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.42009C>T	p.Ser14003Ser	synonymous	Exon 70 of 84	ENSP00000381008.2	Q8WXI7
	MUC16	ENST00000711672.1		c.42195C>T	p.Ser14065Ser	synonymous	Exon 74 of 88	ENSP00000518832.1	A0AAA9YHI4
	MUC16	ENST00000710609.1		c.42129C>T	p.Ser14043Ser	synonymous	Exon 73 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3070 AN: 152060 Hom.: 40 Cov.: 31

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0183 AC: 4459 AN: 243328 AF XY: 0.0191

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.00661

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00842

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0230 AC: 33447 AN: 1456338 Hom.: 470 Cov.: 32 AF XY: 0.0232 AC XY: 16772 AN XY: 724374

African (AFR) AF: 0.0206 AC: 684 AN: 33250

American (AMR) AF: 0.00776 AC: 343 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 295 AN: 25952

East Asian (EAS) AF: 0.00975 AC: 382 AN: 39168

South Asian (SAS) AF: 0.0220 AC: 1882 AN: 85484

European-Finnish (FIN) AF: 0.0116 AC: 619 AN: 53256

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5740

European-Non Finnish (NFE) AF: 0.0253 AC: 28009 AN: 1109096

Other (OTH) AF: 0.0192 AC: 1156 AN: 60178

GnomAD4 genome AF: 0.0202 AC: 3072 AN: 152178 Hom.: 40 Cov.: 31 AF XY: 0.0194 AC XY: 1443 AN XY: 74396

African (AFR) AF: 0.0214 AC: 888 AN: 41520

American (AMR) AF: 0.0148 AC: 226 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5168

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4818

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1634 AN: 67994

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0226 Hom.: 20

Bravo AF: 0.0209

Asia WGS AF: 0.0140 AC: 48 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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.016
DANN	Benign	0.48
PhyloP100		-7.1
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: rs76124866; hg19: chr19-8982266;