8-6499786-T-C

Position:

• chr8-6499786-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001118887.2(ANGPT2):​c.*3315A>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 0.32 in 1,429,614 control chromosomes in the GnomAD database, including 78,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5822 hom., cov: 32)
  • Exomes 𝑓: 0.33 (72797 hom.)
• Consequence: ANGPT2 NM_001118887.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.210

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-6499786-T-C is Benign according to our data. Variant chr8-6499786-T-C is described in ClinVar as [Benign]. Clinvar id is 1175465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPT2	NM_001118887.2	c.*3315A>G		3_prime_UTR_variant	9/9	ENST00000629816.3
MCPH1	NM_024596.5	c.2137-66T>C		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPT2	ENST00000629816.3	c.*3315A>G		3_prime_UTR_variant	9/9	1	NM_001118887.2	P4
MCPH1	ENST00000344683.10	c.2137-66T>C		intron_variant		1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37238 AN: 151986 Hom.: 5826 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.329 AC: 419770 AN: 1277512 Hom.: 72797 Cov.: 18 AF XY: 0.329 AC XY: 212542 AN XY: 645428

Gnomad4 AFR exome AF: 0.0568

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.391

Gnomad4 EAS exome AF: 0.0869

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.245 AC: 37220 AN: 152102 Hom.: 5822 Cov.: 32 AF XY: 0.242 AC XY: 17967 AN XY: 74370

Gnomad4 AFR AF: 0.0615

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.0933

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.281

Alfa AF: 0.204 Hom.: 636

Bravo AF: 0.232

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.81

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: rs2916715; hg19: chr8-6357307;