rs3824312

chr8-6528920-G-Achr8-6528920-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):c.2214+28991G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,144 control chromosomes in the GnomAD database, including 5,370 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 0.25 (5370 hom., cov: 33)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.983

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPT2	NM_001118887.2	c.445-1244C>T		intron_variant		ENST00000629816.3
MCPH1	NM_024596.5	c.2214+28991G>A		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.2214+28991G>A		intron_variant		1	NM_024596.5	P1
ANGPT2	ENST00000629816.3	c.445-1244C>T		intron_variant		1	NM_001118887.2	P4

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37757 AN: 152026 Hom.: 5372 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.294

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

GnomAD4 genome AF: 0.248 AC: 37751 AN: 152144 Hom.: 5370 Cov.: 33 AF XY: 0.247 AC XY: 18367 AN XY: 74366

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.292

Alfa AF: 0.220 Hom.: 951

Bravo AF: 0.242

Asia WGS AF: 0.243 AC: 844 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.012
Dann	Benign	0.68

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: rs3824312; hg19: chr8-6386441;