2-111772467-C-G

Variant names:

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

Variant summary

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

The NM_022662.4(ANAPC1):​c.5593G>C​(p.Asp1865His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 23)
• Consequence: ANAPC1 NM_022662.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>C	p.Asp1865His	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>C	p.Asp1865His	missense	Exon 47 of 48	ENSP00000339109.3	Q9H1A4
	ANAPC1	ENST00000427997.5	TSL:1	c.4195G>C	p.Asp1399His	missense	Exon 36 of 37	ENSP00000396695.1	H0Y564
	ANAPC1	ENST00000917121.1		c.5635G>C	p.Asp1879His	missense	Exon 47 of 48	ENSP00000587180.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	M
PhyloP100		3.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.092
Sift	Benign	0.17	T
Sift4G	Benign	0.26	T
Polyphen		0.84	P
Vest4		0.69
MutPred		0.33		Gain of sheet (P = 0.0827)
MVP		0.22
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.16
gMVP		0.42
Mutation Taster		=81/19	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: rs753847050; hg19: chr2-112530044;