1-212995052-G-C

Variant names:

• chr1-212995052-G-C
• rs770274597
• NM_144567.5:c.1624C>G

Variant summary

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

The NM_144567.5(ANGEL2):​c.1624C>G​(p.Leu542Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANGEL2 NM_144567.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.45

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

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 rank	MANE	Protein	UniProt
ANGEL2	NM_144567.5	c.1624C>G	p.Leu542Val	missense_variant	Exon 9 of 9	ENST00000366962.8	NP_653168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGEL2	ENST00000366962.8	c.1624C>G	p.Leu542Val	missense_variant	Exon 9 of 9	1	NM_144567.5	ENSP00000355929.3
ANGEL2	ENST00000360506.6	c.1117C>G	p.Leu373Val	missense_variant	Exon 8 of 8	1		ENSP00000353696.2
ANGEL2	ENST00000535388.2	c.1117C>G	p.Leu373Val	missense_variant	Exon 8 of 8	1		ENSP00000438141.2
ANGEL2	ENST00000473303.1	n.1812C>G		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1624C>G (p.L542V) alteration is located in exon 9 (coding exon 9) of the ANGEL2 gene. This alteration results from a C to G substitution at nucleotide position 1624, causing the leucine (L) at amino acid position 542 to be replaced by a valine (V). 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	Benign	0.12
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Pathogenic	0.69
Sift	Benign	0.081	T;D;.
Sift4G	Benign	0.14	T;T;T
Polyphen		0.97	D;.;.
Vest4		0.67
MutPred		0.44		Loss of ubiquitination at K539 (P = 0.1037);.;.;
MVP		0.91
MPC		0.73
ClinPred		0.82	D
GERP RS		5.9
Varity_R		0.41
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs770274597; hg19: chr1-213168394;