rs759545352

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_024596.5(MCPH1):c.2210C>G(p.Ala737Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,210 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000083 ( 1 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.29

Variant links:

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]

MCPH1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.2210C>G	p.Ala737Gly	missense_variant	Exon 12 of 14	ENST00000344683.10	NP_078872.3	Q8NEM0-1
ANGPT2	NM_001118887.2 link	c.*3176G>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000629816.3	NP_001112359.1	O15123-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 link	c.2210C>G	p.Ala737Gly	missense_variant	Exon 12 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1
ANGPT2	ENST00000629816 link	c.*3176G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_001118887.2	ENSP00000486858.2		O15123-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000120

AC:

AN:

249562

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000828

AC:

121

AN:

1461004

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

726862

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000112

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000266

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 737 of the MCPH1 protein (p.Ala737Gly). This variant is present in population databases (rs759545352, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MCPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 435836). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. -

Nov 29, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Apr 20, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Nov 19, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2210C>G (p.A737G) alteration is located in exon 12 (coding exon 12) of the MCPH1 gene. This alteration results from a C to G substitution at nucleotide position 2210, causing the alanine (A) at amino acid position 737 to be replaced by a glycine (G). The p.A737G alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Microcephaly 1, primary, autosomal recessive

Uncertain:1

Jun 30, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.26

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.58

MVP

0.68

ClinPred

0.66

GERP RS

4.9

Varity_R

0.63

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over