chr8-6563013-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001118887.2(ANGPT2):​c.-79T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANGPT2 NM_001118887.2 5_prime_UTR_premature_start_codon_gain
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.-79T>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	ENST00000629816.3	NP_001112359.1
ANGPT2	NM_001118887.2	c.-79T>G		5_prime_UTR_variant	Exon 1 of 9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2215-58441A>C		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>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	1	NM_001118887.2	ENSP00000486858.2
ANGPT2	ENST00000629816.3	c.-79T>G		5_prime_UTR_variant	Exon 1 of 9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2215-58441A>C		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1321748 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 647318

African (AFR) AF: 0.00 AC: 0 AN: 29608

American (AMR) AF: 0.00 AC: 0 AN: 32672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20208

East Asian (EAS) AF: 0.00 AC: 0 AN: 37586

South Asian (SAS) AF: 0.00 AC: 0 AN: 69266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4322

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1031846

Other (OTH) AF: 0.00 AC: 0 AN: 54732

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.53
PhyloP100		0.0070
PromoterAI		0.013	Neutral

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

Other links and lift over

dbSNP: rs3739391; hg19: chr8-6420534;