rs762197996

Variant names:

• chr19-8856089-C-T
• rs762197996
• NM_001401501.2:c.43410G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001401501.2(MUC16):​c.43410G>A​(p.Ser14470Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,597,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: MUC16 NM_001401501.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.87
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.003).
• BP6: Variant 19-8856089-C-T is Benign according to our data. Variant chr19-8856089-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2649213.Status of the report is criteria_provided_single_submitter, 1 stars.

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.43410G>A	p.Ser14470Ser	synonymous	Exon 90 of 93	NP_001388430.1	A0AAG2UXK0
	MUC16	NM_001414686.1		c.43836G>A	p.Ser14612Ser	synonymous	Exon 91 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.43290G>A	p.Ser14430Ser	synonymous	Exon 87 of 90	NP_001401616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.43188G>A	p.Ser14396Ser	synonymous	Exon 81 of 84	ENSP00000381008.2	Q8WXI7
	MUC16	ENST00000711672.1		c.43374G>A	p.Ser14458Ser	synonymous	Exon 85 of 88	ENSP00000518832.1	A0AAA9YHI4
	MUC16	ENST00000710609.1		c.43308G>A	p.Ser14436Ser	synonymous	Exon 84 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 8 AN: 222696 AF XY: 0.0000334

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000602

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 90 AN: 1444840 Hom.: 1 Cov.: 31 AF XY: 0.0000642 AC XY: 46 AN XY: 716746

African (AFR) AF: 0.0000301 AC: 1 AN: 33214

American (AMR) AF: 0.00 AC: 0 AN: 41846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25756

East Asian (EAS) AF: 0.00 AC: 0 AN: 39100

South Asian (SAS) AF: 0.0000723 AC: 6 AN: 83004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52516

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5746

European-Non Finnish (NFE) AF: 0.0000634 AC: 70 AN: 1103788

Other (OTH) AF: 0.0000668 AC: 4 AN: 59870

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000567

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
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.056
DANN	Benign	0.86
PhyloP100		-2.9
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: rs762197996; hg19: chr19-8966765; COSMIC: COSV66690291;