chr8-6514712-C-T

Position:

• chr8-6514712-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001118887.2(ANGPT2):​c.994G>A​(p.Val332Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,072 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (10 hom.)
• Consequence: ANGPT2 NM_001118887.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.58

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 (MetaRNN=0.010174364).
• BP6: Variant 8-6514712-C-T is Benign according to our data. Variant chr8-6514712-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00535 (814/152248) while in subpopulation AFR AF= 0.0188 (781/41532). AF 95% confidence interval is 0.0177. There are 5 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 814 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.994G>A	p.Val332Ile	missense_variant	6/9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2214+14783C>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.994G>A	p.Val332Ile	missense_variant	6/9	1	NM_001118887.2	ENSP00000486858	P4
MCPH1	ENST00000344683.10	c.2214+14783C>T		intron_variant		1	NM_024596.5	ENSP00000342924	P1

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152130 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00139 AC: 350 AN: 251462 Hom.: 6 AF XY: 0.00100 AC XY: 136 AN XY: 135900

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000594 AC: 869 AN: 1461824 Hom.: 10 Cov.: 31 AF XY: 0.000501 AC XY: 364 AN XY: 727206

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00535 AC: 814 AN: 152248 Hom.: 5 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74428

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000928 Hom.: 6

Bravo AF: 0.00623

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00178 AC: 216

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T;T;T;T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.0	M;.;.;.
MutationTaster	Benign	0.99	D;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.64	N;.;N;N
REVEL	Benign	0.10
Sift	Benign	0.032	D;.;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.014	B;B;B;B
Vest4		0.28
MVP		0.72
MPC		0.046
ClinPred		0.0094	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.49

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: rs7813215; hg19: chr8-6372233;