rs1035442

Variant names:

• chr19-8851305-C-G
• rs1035442
• NM_001401501.2:c.43618G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-8851305-C-G
• chr19-8851305-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.43618G>C​(p.Val14540Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 1,613,002 control chromosomes in the GnomAD database, including 689,345 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 0.92 (63904 hom., cov: 29)
  • Exomes 𝑓: 0.93 (625441 hom.)
• Consequence: MUC16 NM_001401501.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.233
• Publications: 28 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=6.8387624E-7).
• BP6: Variant 19-8851305-C-G is Benign according to our data. Variant chr19-8851305-C-G is described in ClinVar as Benign. ClinVar VariationId is 3058931.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

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.43618G>C	p.Val14540Leu	missense	Exon 92 of 93	NP_001388430.1	A0AAG2UXK0
	MUC16	NM_001414686.1		c.44044G>C	p.Val14682Leu	missense	Exon 93 of 94	NP_001401615.1
	MUC16	NM_001414687.1		c.43498G>C	p.Val14500Leu	missense	Exon 89 of 90	NP_001401616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC16	ENST00000397910.8	TSL:5	c.43396G>C	p.Val14466Leu	missense	Exon 83 of 84	ENSP00000381008.2	Q8WXI7
	MUC16	ENST00000711672.1		c.43582G>C	p.Val14528Leu	missense	Exon 87 of 88	ENSP00000518832.1	A0AAA9YHI4
	MUC16	ENST00000710609.1		c.43516G>C	p.Val14506Leu	missense	Exon 86 of 87	ENSP00000518375.1	A0AA34QW05

Frequencies

GnomAD3 genomes AF: 0.917 AC: 139342 AN: 152012 Hom.: 63867 Cov.: 29

Gnomad AFR AF: 0.909

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.960

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.945

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.927

Gnomad OTH AF: 0.914

GnomAD2 exomes AF: 0.919 AC: 228028 AN: 248236 AF XY: 0.923

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.854

Gnomad ASJ exome AF: 0.958

Gnomad EAS exome AF: 0.906

Gnomad FIN exome AF: 0.922

Gnomad NFE exome AF: 0.931

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.925 AC: 1351545 AN: 1460872 Hom.: 625441 Cov.: 62 AF XY: 0.927 AC XY: 673443 AN XY: 726764

African (AFR) AF: 0.904 AC: 30236 AN: 33452

American (AMR) AF: 0.853 AC: 38064 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 24976 AN: 26074

East Asian (EAS) AF: 0.913 AC: 36236 AN: 39684

South Asian (SAS) AF: 0.945 AC: 81448 AN: 86188

European-Finnish (FIN) AF: 0.921 AC: 49146 AN: 53338

Middle Eastern (MID) AF: 0.953 AC: 5489 AN: 5760

European-Non Finnish (NFE) AF: 0.927 AC: 1030053 AN: 1111428

Other (OTH) AF: 0.926 AC: 55897 AN: 60336

GnomAD4 genome AF: 0.917 AC: 139437 AN: 152130 Hom.: 63904 Cov.: 29 AF XY: 0.915 AC XY: 68068 AN XY: 74366

African (AFR) AF: 0.909 AC: 37729 AN: 41502

American (AMR) AF: 0.888 AC: 13567 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 3332 AN: 3470

East Asian (EAS) AF: 0.902 AC: 4654 AN: 5158

South Asian (SAS) AF: 0.945 AC: 4552 AN: 4816

European-Finnish (FIN) AF: 0.910 AC: 9641 AN: 10592

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.927 AC: 63051 AN: 68004

Other (OTH) AF: 0.913 AC: 1929 AN: 2112

Alfa AF: 0.926 Hom.: 49302

Bravo AF: 0.912

TwinsUK AF: 0.924 AC: 3427

ALSPAC AF: 0.931 AC: 3587

ESP6500AA AF: 0.915 AC: 3657

ESP6500EA AF: 0.931 AC: 7765

ExAC AF: 0.921 AC: 111321

Asia WGS AF: 0.905 AC: 3149 AN: 3478

EpiCase AF: 0.933

EpiControl AF: 0.934

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	0.066
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.10
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	6.8e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.23
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.035
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.032
ClinPred		0.00030	T
GERP RS		-0.19
gMVP		0.19
Mutation Taster		=96/4	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: rs1035442; hg19: chr19-8961981; COSMIC: COSV107489546;