8-6531459-G-T

Variant names:

• chr8-6531459-G-T
• rs2515478
• NM_024596.5:c.2214+31530G>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+31530G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.658 in 151,512 control chromosomes in the GnomAD database, including 33,242 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 0.66 (33242 hom., cov: 29)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• Publications: 2 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=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.717 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2214+31530G>T		intron	N/A	NP_078872.3	Q8NEM0-1
	ANGPT2	NM_001118887.2	MANE Select	c.444+873C>A		intron	N/A	NP_001112359.1	O15123-3
	MCPH1	NM_001322042.2		c.2214+31530G>T		intron	N/A	NP_001308971.2	A0A8I5KV10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2214+31530G>T		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.444+873C>A		intron	N/A	ENSP00000486858.2	O15123-3
	ANGPT2	ENST00000325203.9	TSL:1	c.444+873C>A		intron	N/A	ENSP00000314897.5	O15123-1

Frequencies

GnomAD3 genomes AF: 0.659 AC: 99697 AN: 151394 Hom.: 33212 Cov.: 29

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.672

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

GnomAD4 genome AF: 0.658 AC: 99767 AN: 151512 Hom.: 33242 Cov.: 29 AF XY: 0.650 AC XY: 48116 AN XY: 73986

African (AFR) AF: 0.577 AC: 23824 AN: 41256

American (AMR) AF: 0.669 AC: 10217 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2367 AN: 3466

East Asian (EAS) AF: 0.537 AC: 2748 AN: 5118

South Asian (SAS) AF: 0.520 AC: 2488 AN: 4788

European-Finnish (FIN) AF: 0.666 AC: 6973 AN: 10476

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.723 AC: 49049 AN: 67854

Other (OTH) AF: 0.666 AC: 1396 AN: 2096

Alfa AF: 0.696 Hom.: 4816

Bravo AF: 0.655

Asia WGS AF: 0.496 AC: 1725 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.53
PhyloP100		-0.028
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: rs2515478; hg19: chr8-6388980;