8-6499714-A-T

Position:

• chr8-6499714-A-T

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.*3387T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 723,324 control chromosomes in the GnomAD database, including 33,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5672 hom., cov: 32)
  • Exomes 𝑓: 0.30 (28164 hom.)
• Consequence: ANGPT2 NM_001118887.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.137

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=-0.77).
• BP6: Variant 8-6499714-A-T is Benign according to our data. Variant chr8-6499714-A-T is described in ClinVar as [Benign]. Clinvar id is 1262416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.*3387T>A		3_prime_UTR_variant	9/9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2137-138A>T		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPT2	ENST00000629816.3	c.*3387T>A		3_prime_UTR_variant	9/9	1	NM_001118887.2	ENSP00000486858	P4
MCPH1	ENST00000344683.10	c.2137-138A>T		intron_variant		1	NM_024596.5	ENSP00000342924	P1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36566 AN: 151974 Hom.: 5676 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.299 AC: 170966 AN: 571232 Hom.: 28164 Cov.: 7 AF XY: 0.299 AC XY: 91479 AN XY: 305510

Gnomad4 AFR exome AF: 0.0633

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.389

Gnomad4 EAS exome AF: 0.0633

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.349

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.240 AC: 36546 AN: 152092 Hom.: 5672 Cov.: 32 AF XY: 0.237 AC XY: 17596 AN XY: 74348

Gnomad4 AFR AF: 0.0597

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.0630

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.277

Alfa AF: 0.280 Hom.: 836

Bravo AF: 0.228

Asia WGS AF: 0.140 AC: 487 AN: 3478

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.2
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: rs2916716; hg19: chr8-6357235;