rs72936240

chr2-111856852-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PVS1 BP6_Moderate

The NM_022662.4(ANAPC1):c.1393C>T(p.Gln465Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.28 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANAPC1 NM_022662.4 stop_gained
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.60

Genes affected

ANAPC1 (HGNC:19988): (anaphase promoting complex subunit 1) This gene encodes a subunit of the anaphase-promoting complex. This complex is an E3 ubiquitin ligase that regulates progression through the metaphase to anaphase portion of the cell cycle by ubiquitinating proteins which targets them for degradation. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 2-111856852-G-A is Benign according to our data. Variant chr2-111856852-G-A is described in ClinVar as [Benign]. Clinvar id is 402367.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANAPC1	NM_022662.4	c.1393C>T	p.Gln465Ter	stop_gained	12/48	ENST00000341068.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANAPC1	ENST00000341068.8	c.1393C>T	p.Gln465Ter	stop_gained	12/48	1	NM_022662.4	P1
ANAPC1	ENST00000482177.1	n.214C>T		non_coding_transcript_exon_variant	1/2	2
ANAPC1	ENST00000427997.5			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0816 AC: 6366 AN: 78002 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0924

Gnomad ASJ AF: 0.0697

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0811

Gnomad OTH AF: 0.132

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.282 AC: 272953 AN: 967794 Hom.: 0 Cov.: 53 AF XY: 0.277 AC XY: 134170 AN XY: 484398

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.0898

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.311

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0816 AC: 6368 AN: 78084 Hom.: 0 Cov.: 33 AF XY: 0.0849 AC XY: 3287 AN XY: 38726

Gnomad4 AFR AF: 0.0601

Gnomad4 AMR AF: 0.0922

Gnomad4 ASJ AF: 0.0697

Gnomad4 EAS AF: 0.0944

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.0811

Gnomad4 OTH AF: 0.130

Alfa AF: 0.213 Hom.: 0

ExAC AF: 0.430 AC: 52254

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0e-37	P
Vest4		0.92
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72936240; hg19: chr2-112614429; COSMIC: COSV61974026; COSMIC: COSV61974026;