2-111772467-C-T

Variant names:

• chr2-111772467-C-T
• rs753847050
• NM_022662.4:c.5593G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022662.4(ANAPC1):​c.5593G>A​(p.Asp1865Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,458,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1865E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ANAPC1 NM_022662.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19
• Publications: 0 publications found

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]

ANAPC1 Gene-Disease associations (from GenCC):

• Rothmund-Thomson syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09913126).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022662.4. 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
	ANAPC1	NM_022662.4	MANE Select	c.5593G>A	p.Asp1865Asn	missense	Exon 47 of 48	NP_073153.1	Q9H1A4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANAPC1	ENST00000341068.8	TSL:1 MANE Select	c.5593G>A	p.Asp1865Asn	missense	Exon 47 of 48	ENSP00000339109.3	Q9H1A4
	ANAPC1	ENST00000427997.5	TSL:1	c.4195G>A	p.Asp1399Asn	missense	Exon 36 of 37	ENSP00000396695.1	H0Y564
	ANAPC1	ENST00000917121.1		c.5635G>A	p.Asp1879Asn	missense	Exon 47 of 48	ENSP00000587180.1

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 145250 Hom.: 0 Cov.: 23

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000301

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000526 AC: 8 AN: 151962 AF XY: 0.0000490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000593

Gnomad OTH exome AF: 0.000275

GnomAD4 exome AF: 0.0000221 AC: 29 AN: 1313532 Hom.: 0 Cov.: 18 AF XY: 0.0000230 AC XY: 15 AN XY: 651738

African (AFR) AF: 0.00 AC: 0 AN: 30114

American (AMR) AF: 0.000191 AC: 7 AN: 36712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22948

East Asian (EAS) AF: 0.00 AC: 0 AN: 37320

South Asian (SAS) AF: 0.00 AC: 0 AN: 77222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51316

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5242

European-Non Finnish (NFE) AF: 0.0000200 AC: 20 AN: 997798

Other (OTH) AF: 0.0000182 AC: 1 AN: 54860

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 145250 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 70426

African (AFR) AF: 0.00 AC: 0 AN: 38828

American (AMR) AF: 0.00 AC: 0 AN: 14382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 4778

South Asian (SAS) AF: 0.00 AC: 0 AN: 4250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66456

Other (OTH) AF: 0.00 AC: 0 AN: 1920

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000250 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.048
Sift	Benign	0.23	T
Sift4G	Benign	0.51	T
Polyphen		0.0020	B
Vest4		0.38
MutPred		0.32		Gain of sheet (P = 0.0827)
MVP		0.088
ClinPred		0.14	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.28
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs753847050; hg19: chr2-112530044; COSMIC: COSV106105901; COSMIC: COSV106105901;