8-6499686-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001118887.2(ANGPT2):c.*3415T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 627,316 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.016 (70 hom.)
• Consequence: ANGPT2 NM_001118887.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0430

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-6499686-A-G is Benign according to our data. Variant chr8-6499686-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1187061.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1995/152326) while in subpopulation NFE AF= 0.019 (1291/68024). AF 95% confidence interval is 0.0181. There are 24 homozygotes in gnomad4. There are 945 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1994 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPT2	NM_001118887.2	c.*3415T>C		3_prime_UTR_variant	9/9	ENST00000629816.3
MCPH1	NM_024596.5	c.2137-166A>G		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPT2	ENST00000629816.3	c.*3415T>C		3_prime_UTR_variant	9/9	1	NM_001118887.2	P4
MCPH1	ENST00000344683.10	c.2137-166A>G		intron_variant		1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1994 AN: 152208 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0201

GnomAD4 exome AF: 0.0156 AC: 7407 AN: 474990 Hom.: 70 Cov.: 5 AF XY: 0.0148 AC XY: 3735 AN XY: 252628

Gnomad4 AFR exome AF: 0.00309

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.00821

Gnomad4 EAS exome AF: 0.0000324

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.0327

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0131 AC: 1995 AN: 152326 Hom.: 24 Cov.: 33 AF XY: 0.0127 AC XY: 945 AN XY: 74484

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0300

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.0135 Hom.: 1

Bravo AF: 0.0113

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.90
Dann	Benign	0.63

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: rs2442474; hg19: chr8-6357207;