8-6499895-C-T

Position:

• chr8-6499895-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_024596.5(MCPH1):​c.2180C>T​(p.Pro727Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00082 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 7.29

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]

MCPH1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34096915).
• BP6: Variant 8-6499895-C-T is Benign according to our data. Variant chr8-6499895-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194122.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2180C>T	p.Pro727Leu	missense_variant	12/14	ENST00000344683.10	NP_078872.3
ANGPT2	NM_001118887.2	c.*3206G>A		3_prime_UTR_variant	9/9	ENST00000629816.3	NP_001112359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2180C>T	p.Pro727Leu	missense_variant	12/14	1	NM_024596.5	ENSP00000342924.5
ANGPT2	ENST00000629816	c.*3206G>A		3_prime_UTR_variant	9/9	1	NM_001118887.2	ENSP00000486858.2

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152104 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000986 AC: 246 AN: 249570 Hom.: 0 AF XY: 0.00102 AC XY: 138 AN XY: 135402

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000956

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.00116 AC: 1692 AN: 1461300 Hom.: 0 Cov.: 30 AF XY: 0.00112 AC XY: 814 AN XY: 726960

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152222 Hom.: 1 Cov.: 33 AF XY: 0.000739 AC XY: 55 AN XY: 74446

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00105 Hom.: 2

Bravo AF: 0.000937

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00121 AC: 10

ExAC AF: 0.00108 AC: 131

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MCPH1: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in twin females with primary microcephaly in the published literature, but a second variant in the MCPH1 gene was not reported in these patients (Pavone et al., 2020); This variant is associated with the following publications: (PMID: 31101089, 32714618) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 06, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. Polyphen and MutationTaster yielded discordant predictions regarding whether this amino acid change is damaging to the protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 727 of the MCPH1 protein (p.Pro727Leu). This variant is present in population databases (rs199861426, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary microcephaly (PMID: 32714618). ClinVar contains an entry for this variant (Variation ID: 194122). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MCPH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Microcephaly 1, primary, autosomal recessive Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Short stature;C3714756:Intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Apr 19, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.85
MVP		0.78
ClinPred		0.19	T
GERP RS		4.0
Varity_R		0.81
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs199861426; hg19: chr8-6357416; COSMIC: COSV57337668; COSMIC: COSV57337668;