8-6539477-G-C

Variant names:

• chr8-6539477-G-C
• rs1823375
• NM_024596.5:c.2214+39548G>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+39548G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 152,030 control chromosomes in the GnomAD database, including 25,574 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 0.56 (25574 hom., cov: 33)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• 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 = 0.664 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2214+39548G>C		intron	N/A	NP_078872.3
	ANGPT2	NM_001118887.2	MANE Select	c.289-6990C>G		intron	N/A	NP_001112359.1
	MCPH1	NM_001322042.2		c.2214+39548G>C		intron	N/A	NP_001308971.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2214+39548G>C		intron	N/A	ENSP00000342924.5
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.289-6990C>G		intron	N/A	ENSP00000486858.2
	ANGPT2	ENST00000325203.9	TSL:1	c.289-6990C>G		intron	N/A	ENSP00000314897.5

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84860 AN: 151912 Hom.: 25565 Cov.: 33

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.554

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

GnomAD4 genome AF: 0.558 AC: 84889 AN: 152030 Hom.: 25574 Cov.: 33 AF XY: 0.561 AC XY: 41728 AN XY: 74318

African (AFR) AF: 0.305 AC: 12642 AN: 41464

American (AMR) AF: 0.596 AC: 9107 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2243 AN: 3472

East Asian (EAS) AF: 0.669 AC: 3450 AN: 5160

South Asian (SAS) AF: 0.621 AC: 2981 AN: 4802

European-Finnish (FIN) AF: 0.648 AC: 6834 AN: 10552

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.669 AC: 45469 AN: 67986

Other (OTH) AF: 0.557 AC: 1178 AN: 2114

Alfa AF: 0.591 Hom.: 3435

Bravo AF: 0.542

Asia WGS AF: 0.634 AC: 2203 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.75
PhyloP100		-0.018
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: rs1823375; hg19: chr8-6396998;