rs2959811

Variant names:

• chr8-6534045-C-A
• rs2959811
• NM_024596.5:c.2214+34116C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6534045-C-A
• chr8-6534045-C-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+34116C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 151,814 control chromosomes in the GnomAD database, including 9,593 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 0.35 (9593 hom., cov: 30)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2214+34116C>A		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3
ANGPT2	NM_001118887.2	c.289-1558G>T		intron_variant	Intron 1 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+34116C>A		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5
ANGPT2	ENST00000629816.3	c.289-1558G>T		intron_variant	Intron 1 of 8	1	NM_001118887.2	ENSP00000486858.2

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52755 AN: 151694 Hom.: 9583 Cov.: 30

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.333

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

GnomAD4 genome AF: 0.348 AC: 52793 AN: 151814 Hom.: 9593 Cov.: 30 AF XY: 0.343 AC XY: 25444 AN XY: 74148

African (AFR) AF: 0.275 AC: 11389 AN: 41404

American (AMR) AF: 0.378 AC: 5768 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1244 AN: 3464

East Asian (EAS) AF: 0.131 AC: 675 AN: 5166

South Asian (SAS) AF: 0.281 AC: 1351 AN: 4810

European-Finnish (FIN) AF: 0.387 AC: 4070 AN: 10510

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27251 AN: 67896

Other (OTH) AF: 0.330 AC: 696 AN: 2106

Alfa AF: 0.254 Hom.: 672

Bravo AF: 0.340

Asia WGS AF: 0.210 AC: 736 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.83
PhyloP100		-0.014
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2959811; hg19: chr8-6391566;