8-6507401-T-C

Variant names:

• chr8-6507401-T-C
• rs2515409
• NM_024596.5:c.2214+7472T>C

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+7472T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,098 control chromosomes in the GnomAD database, including 3,571 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 0.19 (3571 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.662
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2214+7472T>C		intron	N/A	NP_078872.3
	ANGPT2	NM_001118887.2	MANE Select	c.1327+1531A>G		intron	N/A	NP_001112359.1
	MCPH1	NM_001322042.2		c.2214+7472T>C		intron	N/A	NP_001308971.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2214+7472T>C		intron	N/A	ENSP00000342924.5
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.1327+1531A>G		intron	N/A	ENSP00000486858.2
	ANGPT2	ENST00000325203.9	TSL:1	c.1330+1531A>G		intron	N/A	ENSP00000314897.5

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28485 AN: 151980 Hom.: 3555 Cov.: 32

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0759

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.161

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

GnomAD4 genome AF: 0.188 AC: 28545 AN: 152098 Hom.: 3571 Cov.: 32 AF XY: 0.186 AC XY: 13797 AN XY: 74356

African (AFR) AF: 0.358 AC: 14821 AN: 41448

American (AMR) AF: 0.114 AC: 1748 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 349 AN: 3472

East Asian (EAS) AF: 0.0761 AC: 394 AN: 5178

South Asian (SAS) AF: 0.174 AC: 838 AN: 4820

European-Finnish (FIN) AF: 0.135 AC: 1432 AN: 10578

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8546 AN: 67994

Other (OTH) AF: 0.159 AC: 337 AN: 2114

Alfa AF: 0.146 Hom.: 6229

Bravo AF: 0.192

Asia WGS AF: 0.154 AC: 536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.6
DANN	Benign	0.72
PhyloP100		0.66
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: rs2515409; hg19: chr8-6364922;