1-212995121-A-G

Position:

• chr1-212995121-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000366962.8(ANGEL2):​c.1555T>C​(p.Trp519Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ANGEL2 ENST00000366962.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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]

ANGEL2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGEL2	NM_144567.5	c.1555T>C	p.Trp519Arg	missense_variant	9/9	ENST00000366962.8	NP_653168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGEL2	ENST00000366962.8	c.1555T>C	p.Trp519Arg	missense_variant	9/9	1	NM_144567.5	ENSP00000355929.3
ANGEL2	ENST00000360506.6	c.1048T>C	p.Trp350Arg	missense_variant	8/8	1		ENSP00000353696.2
ANGEL2	ENST00000535388.2	c.1048T>C	p.Trp350Arg	missense_variant	8/8	1		ENSP00000438141.2
ANGEL2	ENST00000473303.1	n.1743T>C		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460114 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726448

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2024

The c.1555T>C (p.W519R) alteration is located in exon 9 (coding exon 9) of the ANGEL2 gene. This alteration results from a T to C substitution at nucleotide position 1555, causing the tryptophan (W) at amino acid position 519 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.46	T;.;T
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.58	N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	D;D;.
REVEL	Uncertain	0.43
Sift	Benign	0.37	T;T;.
Sift4G	Benign	0.56	T;T;T
Polyphen		0.0060	B;.;.
Vest4		0.54
MutPred		0.50		Gain of disorder (P = 0.0056);.;.;
MVP		0.78
MPC		0.82
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.58
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs966373481; hg19: chr1-213168463;