8-6526078-A-G

Variant names:

• chr8-6526078-A-G
• rs2515462
• NM_024596.5:c.2214+26149A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):​c.2214+26149A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 151,562 control chromosomes in the GnomAD database, including 34,231 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.67 (34231 hom., cov: 29)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.82
• Publications: 9 publications found

Genes affected

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]

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]

ANGPT2 Gene-Disease associations (from GenCC):

• lymphatic malformation 10

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2214+26149A>G		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3
ANGPT2	NM_001118887.2	c.566+1477T>C		intron_variant	Intron 3 of 8	ENST00000629816.3	NP_001112359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2214+26149A>G		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5
ANGPT2	ENST00000629816.3	c.566+1477T>C		intron_variant	Intron 3 of 8	1	NM_001118887.2	ENSP00000486858.2

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101094 AN: 151444 Hom.: 34220 Cov.: 29

Gnomad AFR AF: 0.585

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.706

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.667 AC: 101157 AN: 151562 Hom.: 34231 Cov.: 29 AF XY: 0.676 AC XY: 50021 AN XY: 74038

African (AFR) AF: 0.585 AC: 24118 AN: 41240

American (AMR) AF: 0.688 AC: 10465 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 2506 AN: 3462

East Asian (EAS) AF: 0.944 AC: 4871 AN: 5160

South Asian (SAS) AF: 0.767 AC: 3682 AN: 4798

European-Finnish (FIN) AF: 0.703 AC: 7381 AN: 10492

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.673 AC: 45714 AN: 67898

Other (OTH) AF: 0.708 AC: 1485 AN: 2096

Alfa AF: 0.670 Hom.: 88135

Bravo AF: 0.664

Asia WGS AF: 0.822 AC: 2858 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.58
DANN	Benign	0.27
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2515462; hg19: chr8-6383599;