8-6532368-C-G

Position:

• chr8-6532368-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001118887.2(ANGPT2):​c.408G>C​(p.Ala136Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,613,646 control chromosomes in the GnomAD database, including 76,320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A136A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.31 (7486 hom., cov: 30)
  • Exomes 𝑓: 0.30 (68834 hom.)
• Consequence: ANGPT2 NM_001118887.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -2.49

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-6532368-C-G is Benign according to our data. Variant chr8-6532368-C-G is described in ClinVar as [Benign]. Clinvar id is 158840.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-6532368-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.408G>C	p.Ala136Ala	synonymous_variant	2/9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2214+32439C>G		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPT2	ENST00000629816.3	c.408G>C	p.Ala136Ala	synonymous_variant	2/9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2214+32439C>G		intron_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46933 AN: 151750 Hom.: 7470 Cov.: 30

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.304

GnomAD3 exomes AF: 0.334 AC: 83983 AN: 251380 Hom.: 14898 AF XY: 0.338 AC XY: 45870 AN XY: 135874

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.461

Gnomad SAS exome AF: 0.470

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.301 AC: 439508 AN: 1461778 Hom.: 68834 Cov.: 63 AF XY: 0.305 AC XY: 221944 AN XY: 727186

Gnomad4 AFR exome AF: 0.316

Gnomad4 AMR exome AF: 0.350

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.447

Gnomad4 SAS exome AF: 0.464

Gnomad4 FIN exome AF: 0.323

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.319

GnomAD4 genome AF: 0.309 AC: 46973 AN: 151868 Hom.: 7486 Cov.: 30 AF XY: 0.318 AC XY: 23604 AN XY: 74200

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.463

Gnomad4 SAS AF: 0.480

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.310

Alfa AF: 0.173 Hom.: 1003

EpiCase AF: 0.275

EpiControl AF: 0.282

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.041
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs6559167; hg19: chr8-6389889; COSMIC: COSV57334992;