rs2515488

Positions:

• chr8-6545485-A-C
• chr8-6545485-A-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+45556A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 152,116 control chromosomes in the GnomAD database, including 18,809 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 0.49 (18809 hom., cov: 33)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.596

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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.289-12998T>G		intron_variant		ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2214+45556A>C		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2214+45556A>C		intron_variant		1	NM_024596.5	ENSP00000342924	P1
ANGPT2	ENST00000629816.3	c.289-12998T>G		intron_variant		1	NM_001118887.2	ENSP00000486858	P4

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75154 AN: 151998 Hom.: 18773 Cov.: 33

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.503

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

GnomAD4 genome AF: 0.495 AC: 75240 AN: 152116 Hom.: 18809 Cov.: 33 AF XY: 0.495 AC XY: 36852 AN XY: 74378

Gnomad4 AFR AF: 0.573

Gnomad4 AMR AF: 0.476

Gnomad4 ASJ AF: 0.441

Gnomad4 EAS AF: 0.506

Gnomad4 SAS AF: 0.541

Gnomad4 FIN AF: 0.448

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.506

Alfa AF: 0.473 Hom.: 16728

Bravo AF: 0.497

Asia WGS AF: 0.544 AC: 1894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.82

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: rs2515488; hg19: chr8-6403006;