8-6563013-A-G

Variant names:

• chr8-6563013-A-G
• rs3739391
• NM_001118887.2:c.-79T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 25 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD 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=-0.88).
• 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 rank	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.-79T>C		5_prime_UTR_variant	Exon 1 of 9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2215-58441A>G		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT2	ENST00000629816.3	c.-79T>C		5_prime_UTR_variant	Exon 1 of 9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2215-58441A>G		intron_variant	Intron 12 of 13	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

African (AFR) AF: 0.321 AC: 9504 AN: 29576

American (AMR) AF: 0.785 AC: 25629 AN: 32632

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 15866 AN: 20174

East Asian (EAS) AF: 0.825 AC: 30982 AN: 37568

South Asian (SAS) AF: 0.754 AC: 52101 AN: 69138

European-Finnish (FIN) AF: 0.828 AC: 34339 AN: 41466

Middle Eastern (MID) AF: 0.794 AC: 3428 AN: 4318

European-Non Finnish (NFE) AF: 0.850 AC: 875836 AN: 1030818

Other (OTH) AF: 0.793 AC: 43358 AN: 54662

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

African (AFR) AF: 0.345 AC: 14297 AN: 41462

American (AMR) AF: 0.770 AC: 11775 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2674 AN: 3472

East Asian (EAS) AF: 0.819 AC: 4227 AN: 5162

South Asian (SAS) AF: 0.753 AC: 3633 AN: 4824

European-Finnish (FIN) AF: 0.821 AC: 8707 AN: 10602

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.849 AC: 57742 AN: 68010

Other (OTH) AF: 0.727 AC: 1535 AN: 2112

Alfa AF: 0.805 Hom.: 215966

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
PhyloP100		0.0070
PromoterAI		0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3739391; hg19: chr8-6420534;