1-212997220-C-T

Variant names:

• chr1-212997220-C-T
• rs982573649
• NM_144567.5:c.1418G>A

Variant summary

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

The NM_144567.5(ANGEL2):​c.1418G>A​(p.Arg473Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ANGEL2 NM_144567.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69
• Publications: 0 publications found

Genes affected

ANGEL2 (HGNC:30534): (angel homolog 2) Enables mRNA 3'-UTR binding activity. Involved in 3'-UTR-mediated mRNA stabilization and negative regulation of mitotic cell cycle. Located in Cajal body and cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2301017).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144567.5. 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
	ANGEL2	NM_144567.5	MANE Select	c.1418G>A	p.Arg473Gln	missense	Exon 8 of 9	NP_653168.2
	ANGEL2	NM_001300753.2		c.1040G>A	p.Arg347Gln	missense	Exon 8 of 9	NP_001287682.1
	ANGEL2	NM_001300755.2		c.1040G>A	p.Arg347Gln	missense	Exon 8 of 9	NP_001287684.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGEL2	ENST00000366962.8	TSL:1 MANE Select	c.1418G>A	p.Arg473Gln	missense	Exon 8 of 9	ENSP00000355929.3	Q5VTE6-1
	ANGEL2	ENST00000360506.6	TSL:1	c.911G>A	p.Arg304Gln	missense	Exon 7 of 8	ENSP00000353696.2	Q5VTE6-2
	ANGEL2	ENST00000535388.2	TSL:1	c.911G>A	p.Arg304Gln	missense	Exon 7 of 8	ENSP00000438141.2	Q5VTE6-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.00000398 AC: 1 AN: 251328 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461658 Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111850

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74270

African (AFR) AF: 0.0000242 AC: 1 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

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	0.14
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.32
Sift	Benign	0.21	T
Sift4G	Benign	0.36	T
Polyphen		0.13	B
Vest4		0.097
MutPred		0.61		Loss of methylation at R473 (P = 0.0728)
MVP		0.71
MPC		0.44
ClinPred		0.72	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.59
Mutation Taster		=70/30	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: rs982573649; hg19: chr1-213170562; COSMIC: COSV64737165;