rs3824310

Variant names:

• chr8-6528729-T-C
• rs3824310
• NM_024596.5:c.2214+28800T>C

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+28800T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,250 control chromosomes in the GnomAD database, including 5,339 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 (5339 hom., cov: 34)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 7 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.313 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+28800T>C		intron	N/A	NP_078872.3	Q8NEM0-1
	ANGPT2	NM_001118887.2	MANE Select	c.445-1053A>G		intron	N/A	NP_001112359.1	O15123-3
	MCPH1	NM_001322042.2		c.2214+28800T>C		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+28800T>C		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.445-1053A>G		intron	N/A	ENSP00000486858.2	O15123-3
	ANGPT2	ENST00000325203.9	TSL:1	c.445-1053A>G		intron	N/A	ENSP00000314897.5	O15123-1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37928 AN: 152132 Hom.: 5341 Cov.: 34

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.297

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

GnomAD4 genome AF: 0.249 AC: 37923 AN: 152250 Hom.: 5339 Cov.: 34 AF XY: 0.248 AC XY: 18452 AN XY: 74428

African (AFR) AF: 0.112 AC: 4668 AN: 41564

American (AMR) AF: 0.267 AC: 4078 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1106 AN: 3466

East Asian (EAS) AF: 0.265 AC: 1371 AN: 5180

South Asian (SAS) AF: 0.243 AC: 1175 AN: 4826

European-Finnish (FIN) AF: 0.284 AC: 3009 AN: 10592

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21548 AN: 68006

Other (OTH) AF: 0.294 AC: 621 AN: 2112

Alfa AF: 0.297 Hom.: 26560

Bravo AF: 0.242

Asia WGS AF: 0.246 AC: 855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.5
DANN	Benign	0.53
PhyloP100		1.1
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: rs3824310; hg19: chr8-6386250;