rs2442631

Variant names:

• chr8-6511255-C-T
• rs2442631
• NM_024596.5:c.2214+11326C>T

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+11326C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 151,632 control chromosomes in the GnomAD database, including 14,062 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 0.43 (14062 hom., cov: 31)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2214+11326C>T		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3
ANGPT2	NM_001118887.2	c.1197-2193G>A		intron_variant	Intron 7 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+11326C>T		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5
ANGPT2	ENST00000629816.3	c.1197-2193G>A		intron_variant	Intron 7 of 8	1	NM_001118887.2	ENSP00000486858.2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64718 AN: 151518 Hom.: 14061 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.427 AC: 64744 AN: 151632 Hom.: 14062 Cov.: 31 AF XY: 0.422 AC XY: 31249 AN XY: 74096

African (AFR) AF: 0.448 AC: 18514 AN: 41322

American (AMR) AF: 0.338 AC: 5135 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1526 AN: 3468

East Asian (EAS) AF: 0.219 AC: 1137 AN: 5184

South Asian (SAS) AF: 0.398 AC: 1914 AN: 4810

European-Finnish (FIN) AF: 0.426 AC: 4434 AN: 10412

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30645 AN: 67910

Other (OTH) AF: 0.448 AC: 945 AN: 2110

Alfa AF: 0.445 Hom.: 33032

Bravo AF: 0.422

Asia WGS AF: 0.290 AC: 1008 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.46
PhyloP100		-0.0090
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: rs2442631; hg19: chr8-6368776;