2-111772473-C-G

Variant names:

• chr2-111772473-C-G
• rs757342710
• NM_022662.4:c.5587G>C

Variant summary

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

The NM_022662.4(ANAPC1):​c.5587G>C​(p.Gly1863Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000283 in 1,414,122 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: ANAPC1 NM_022662.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.91
• Publications: 2 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.5587G>C	p.Gly1863Arg	missense splice_region	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.5587G>C	p.Gly1863Arg	missense splice_region	Exon 47 of 48	ENSP00000339109.3	Q9H1A4
	ANAPC1	ENST00000427997.5	TSL:1	c.4189G>C	p.Gly1397Arg	missense splice_region	Exon 36 of 37	ENSP00000396695.1	H0Y564
	ANAPC1	ENST00000917121.1		c.5629G>C	p.Gly1877Arg	missense	Exon 47 of 48	ENSP00000587180.1

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 144802 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000518

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000152 AC: 2 AN: 131686 AF XY: 0.0000142

Gnomad AFR exome AF: 0.000228

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1269320 Hom.: 0 Cov.: 16 AF XY: 0.00000159 AC XY: 1 AN XY: 629496

African (AFR) AF: 0.0000691 AC: 2 AN: 28934

American (AMR) AF: 0.00 AC: 0 AN: 34054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21862

East Asian (EAS) AF: 0.00 AC: 0 AN: 36698

South Asian (SAS) AF: 0.00 AC: 0 AN: 74288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5090

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 964742

Other (OTH) AF: 0.00 AC: 0 AN: 53166

GnomAD4 genome AF: 0.0000138 AC: 2 AN: 144802 Hom.: 0 Cov.: 23 AF XY: 0.0000142 AC XY: 1 AN XY: 70196

African (AFR) AF: 0.0000518 AC: 2 AN: 38604

American (AMR) AF: 0.00 AC: 0 AN: 14354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4774

South Asian (SAS) AF: 0.00 AC: 0 AN: 4256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9958

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66330

Other (OTH) AF: 0.00 AC: 0 AN: 1914

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000251 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.090
Sift	Benign	0.034	D
Sift4G	Benign	0.47	T
Polyphen		0.93	P
Vest4		0.74
MutPred		0.39		Gain of helix (P = 0.0696)
MVP		0.46
ClinPred		0.48	T
GERP RS		4.3
Varity_R		0.088
gMVP		0.32
Mutation Taster		=83/17	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: rs757342710; hg19: chr2-112530050;