8-6513955-C-T

Variant names:

• chr8-6513955-C-T
• rs1982386
• NM_024596.5:c.2214+14026C>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+14026C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,050,550 control chromosomes in the GnomAD database, including 44,882 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 0.27 (6263 hom., cov: 33)
  • Exomes 𝑓: 0.28 (38619 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 9 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2214+14026C>T		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3
ANGPT2	NM_001118887.2	c.1030-111G>A		intron_variant	Intron 6 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+14026C>T		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5
ANGPT2	ENST00000629816.3	c.1030-111G>A		intron_variant	Intron 6 of 8	1	NM_001118887.2	ENSP00000486858.2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40522 AN: 152002 Hom.: 6256 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.277 AC: 248917 AN: 898428 Hom.: 38619 AF XY: 0.280 AC XY: 125904 AN XY: 450368

African (AFR) AF: 0.179 AC: 3502 AN: 19540

American (AMR) AF: 0.390 AC: 8138 AN: 20852

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 5416 AN: 16504

East Asian (EAS) AF: 0.686 AC: 22266 AN: 32436

South Asian (SAS) AF: 0.383 AC: 18608 AN: 48542

European-Finnish (FIN) AF: 0.283 AC: 11735 AN: 41414

Middle Eastern (MID) AF: 0.298 AC: 1124 AN: 3770

European-Non Finnish (NFE) AF: 0.246 AC: 166047 AN: 675012

Other (OTH) AF: 0.299 AC: 12081 AN: 40358

GnomAD4 genome AF: 0.267 AC: 40547 AN: 152122 Hom.: 6263 Cov.: 33 AF XY: 0.278 AC XY: 20697 AN XY: 74358

African (AFR) AF: 0.178 AC: 7398 AN: 41514

American (AMR) AF: 0.364 AC: 5566 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1111 AN: 3472

East Asian (EAS) AF: 0.699 AC: 3611 AN: 5168

South Asian (SAS) AF: 0.397 AC: 1915 AN: 4818

European-Finnish (FIN) AF: 0.296 AC: 3126 AN: 10572

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16758 AN: 67976

Other (OTH) AF: 0.287 AC: 607 AN: 2114

Alfa AF: 0.230 Hom.: 2050

Bravo AF: 0.270

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.5
DANN	Benign	0.48
PhyloP100		0.0060
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: rs1982386; hg19: chr8-6371476;