rs3020221

Variant names:

• chr8-6521242-C-T
• rs3020221
• NM_001118887.2:c.735G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001118887.2(ANGPT2):​c.735G>A​(p.Gln245Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,613,280 control chromosomes in the GnomAD database, including 109,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (9359 hom., cov: 32)
  • Exomes 𝑓: 0.37 (99713 hom.)
• Consequence: ANGPT2 NM_001118887.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0810
• Publications: 27 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: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 8-6521242-C-T is Benign according to our data. Variant chr8-6521242-C-T is described in ClinVar as Benign. ClinVar VariationId is 158838.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.081 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001118887.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPT2	NM_001118887.2	MANE Select	c.735G>A	p.Gln245Gln	synonymous	Exon 4 of 9	NP_001112359.1	O15123-3
	MCPH1	NM_024596.5	MANE Select	c.2214+21313C>T		intron	N/A	NP_078872.3	Q8NEM0-1
	ANGPT2	NM_001147.3		c.735G>A	p.Gln245Gln	synonymous	Exon 4 of 9	NP_001138.1	O15123-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.735G>A	p.Gln245Gln	synonymous	Exon 4 of 9	ENSP00000486858.2	O15123-3
	ANGPT2	ENST00000325203.9	TSL:1	c.735G>A	p.Gln245Gln	synonymous	Exon 4 of 9	ENSP00000314897.5	O15123-1
	ANGPT2	ENST00000523120.2	TSL:1	c.735G>A	p.Gln245Gln	synonymous	Exon 4 of 8	ENSP00000428023.1	E7EVQ3

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52902 AN: 151912 Hom.: 9357 Cov.: 32

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.340 AC: 85543 AN: 251312 AF XY: 0.347

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.240

Gnomad FIN exome AF: 0.332

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.367 AC: 536096 AN: 1461250 Hom.: 99713 Cov.: 44 AF XY: 0.368 AC XY: 267566 AN XY: 726946

African (AFR) AF: 0.338 AC: 11308 AN: 33460

American (AMR) AF: 0.248 AC: 11102 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 9884 AN: 26124

East Asian (EAS) AF: 0.243 AC: 9641 AN: 39626

South Asian (SAS) AF: 0.350 AC: 30227 AN: 86246

European-Finnish (FIN) AF: 0.336 AC: 17934 AN: 53352

Middle Eastern (MID) AF: 0.447 AC: 2577 AN: 5764

European-Non Finnish (NFE) AF: 0.380 AC: 421969 AN: 1111584

Other (OTH) AF: 0.355 AC: 21454 AN: 60374

GnomAD4 genome AF: 0.348 AC: 52927 AN: 152030 Hom.: 9359 Cov.: 32 AF XY: 0.344 AC XY: 25555 AN XY: 74294

African (AFR) AF: 0.335 AC: 13893 AN: 41464

American (AMR) AF: 0.285 AC: 4356 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1295 AN: 3466

East Asian (EAS) AF: 0.238 AC: 1233 AN: 5174

South Asian (SAS) AF: 0.334 AC: 1612 AN: 4832

European-Finnish (FIN) AF: 0.339 AC: 3567 AN: 10536

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25747 AN: 67966

Other (OTH) AF: 0.370 AC: 778 AN: 2104

Alfa AF: 0.372 Hom.: 17149

Bravo AF: 0.345

Asia WGS AF: 0.267 AC: 927 AN: 3476

EpiCase AF: 0.393

EpiControl AF: 0.391

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.3
DANN	Benign	0.65
PhyloP100		-0.081
Mutation Taster		=98/2	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: rs3020221; hg19: chr8-6378763; COSMIC: COSV57336680;