8-6563013-A-G

Position:

• chr8-6563013-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001118887.2(ANGPT2):​c.-79T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,472,494 control chromosomes in the GnomAD database, including 495,939 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 0.69 (40334 hom., cov: 32)
  • Exomes 𝑓: 0.83 (455605 hom.)
• Consequence: ANGPT2 NM_001118887.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.-79T>C		5_prime_UTR_variant	1/9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2215-58441A>G		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPT2	ENST00000629816.3	c.-79T>C		5_prime_UTR_variant	1/9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2215-58441A>G		intron_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105542 AN: 152024 Hom.: 40333 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.849

Gnomad OTH AF: 0.723

GnomAD4 exome AF: 0.826 AC: 1091043 AN: 1320352 Hom.: 455605 Cov.: 19 AF XY: 0.826 AC XY: 534281 AN XY: 646610

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.785

Gnomad4 ASJ exome AF: 0.786

Gnomad4 EAS exome AF: 0.825

Gnomad4 SAS exome AF: 0.754

Gnomad4 FIN exome AF: 0.828

Gnomad4 NFE exome AF: 0.850

Gnomad4 OTH exome AF: 0.793

GnomAD4 genome AF: 0.694 AC: 105556 AN: 152142 Hom.: 40334 Cov.: 32 AF XY: 0.696 AC XY: 51755 AN XY: 74374

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.770

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.753

Gnomad4 FIN AF: 0.821

Gnomad4 NFE AF: 0.849

Gnomad4 OTH AF: 0.727

Alfa AF: 0.824 Hom.: 105588

Bravo AF: 0.677

Asia WGS AF: 0.750 AC: 2607 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.4
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3739391; hg19: chr8-6420534;