8-6499852-G-T

Position:

• chr8-6499852-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024596.5(MCPH1):​c.2137G>T​(p.Val713Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCPH1 NM_024596.5 missense, splice_region
• Scores: Splicing: ADA: 0.8609
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.2137G>T	p.Val713Leu	missense_variant, splice_region_variant	12/14	ENST00000344683.10
ANGPT2	NM_001118887.2	c.*3249C>A		3_prime_UTR_variant	9/9	ENST00000629816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.2137G>T	p.Val713Leu	missense_variant, splice_region_variant	12/14	1	NM_024596.5	P1
ANGPT2	ENST00000629816.3	c.*3249C>A		3_prime_UTR_variant	9/9	1	NM_001118887.2	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Benign	0.037	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.34		Loss of helix (P = 0.0376);
MVP		0.58
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.42
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1811809746; hg19: chr8-6357373;