8-6514651-T-C

Variant names:

• chr8-6514651-T-C
• rs2979671
• NM_024596.5:c.2214+14722T>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+14722T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,593,554 control chromosomes in the GnomAD database, including 111,897 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 0.36 (10156 hom., cov: 32)
  • Exomes 𝑓: 0.37 (101741 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410
• Publications: 8 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2214+14722T>C		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3
ANGPT2	NM_001118887.2	c.1029+26A>G		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+14722T>C		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5
ANGPT2	ENST00000629816.3	c.1029+26A>G		intron_variant	Intron 6 of 8	1	NM_001118887.2	ENSP00000486858.2

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55011 AN: 151932 Hom.: 10156 Cov.: 32

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.387

GnomAD2 exomes AF: 0.346 AC: 86651 AN: 250664 AF XY: 0.353

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.372

Gnomad EAS exome AF: 0.215

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.373 AC: 537283 AN: 1441504 Hom.: 101741 Cov.: 25 AF XY: 0.374 AC XY: 268575 AN XY: 718106

African (AFR) AF: 0.382 AC: 12624 AN: 33048

American (AMR) AF: 0.251 AC: 11216 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9702 AN: 26004

East Asian (EAS) AF: 0.229 AC: 9073 AN: 39560

South Asian (SAS) AF: 0.364 AC: 31191 AN: 85736

European-Finnish (FIN) AF: 0.338 AC: 17986 AN: 53266

Middle Eastern (MID) AF: 0.462 AC: 2644 AN: 5726

European-Non Finnish (NFE) AF: 0.385 AC: 421299 AN: 1093866

Other (OTH) AF: 0.361 AC: 21548 AN: 59674

GnomAD4 genome AF: 0.362 AC: 55027 AN: 152050 Hom.: 10156 Cov.: 32 AF XY: 0.357 AC XY: 26524 AN XY: 74314

African (AFR) AF: 0.377 AC: 15631 AN: 41444

American (AMR) AF: 0.292 AC: 4468 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1278 AN: 3468

East Asian (EAS) AF: 0.216 AC: 1117 AN: 5170

South Asian (SAS) AF: 0.345 AC: 1665 AN: 4830

European-Finnish (FIN) AF: 0.339 AC: 3587 AN: 10574

Middle Eastern (MID) AF: 0.483 AC: 140 AN: 290

European-Non Finnish (NFE) AF: 0.383 AC: 26021 AN: 67964

Other (OTH) AF: 0.383 AC: 807 AN: 2108

Alfa AF: 0.376 Hom.: 4748

Bravo AF: 0.361

Asia WGS AF: 0.259 AC: 900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		0.041
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: rs2979671; hg19: chr8-6372172; COSMIC: COSV57337259;