rs2515413

Variant names:

• chr8-6508099-T-C
• rs2515413
• ENST00000523120.2:c.*780A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000523120.2(ANGPT2):​c.*780A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 152,032 control chromosomes in the GnomAD database, including 8,218 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (8218 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANGPT2 ENST00000523120.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.548
• Publications: 5 publications found

Genes affected

ANGPT2 (HGNC:485): (angiopoietin 2) This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MCPH1 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000523120.2. 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
	MCPH1	NM_024596.5	MANE Select	c.2214+8170T>C		intron	N/A	NP_078872.3	Q8NEM0-1
	ANGPT2	NM_001118887.2	MANE Select	c.1327+833A>G		intron	N/A	NP_001112359.1	O15123-3
	MCPH1	NM_001322042.2		c.2214+8170T>C		intron	N/A	NP_001308971.2	A0A8I5KV10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPT2	ENST00000523120.2	TSL:1	c.*780A>G		3_prime_UTR	Exon 8 of 8	ENSP00000428023.1	E7EVQ3
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2214+8170T>C		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.1327+833A>G		intron	N/A	ENSP00000486858.2	O15123-3

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41708 AN: 151914 Hom.: 8190 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.244

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.275 AC: 41789 AN: 152032 Hom.: 8218 Cov.: 32 AF XY: 0.272 AC XY: 20250 AN XY: 74336

African (AFR) AF: 0.564 AC: 23371 AN: 41448

American (AMR) AF: 0.169 AC: 2576 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 430 AN: 3468

East Asian (EAS) AF: 0.209 AC: 1081 AN: 5184

South Asian (SAS) AF: 0.271 AC: 1305 AN: 4822

European-Finnish (FIN) AF: 0.163 AC: 1730 AN: 10582

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10631 AN: 67964

Other (OTH) AF: 0.243 AC: 512 AN: 2108

Alfa AF: 0.187 Hom.: 5715

Bravo AF: 0.285

Asia WGS AF: 0.237 AC: 827 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.42
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2515413;

hg19: chr8-6365620;