Variant rs35402812 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024596.5(MCPH1):c.1742A>G(p.Glu581Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,244 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 2 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.560

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:

MCPH1 (HGNC:):

MCPH1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04327041).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5 linkuse as main transcript	c.1742A>G	p.Glu581Gly	missense_variant	8/14	ENST00000344683.10	NP_078872.3	Q8NEM0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 linkuse as main transcript	c.1742A>G	p.Glu581Gly	missense_variant	8/14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152282

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000482

AC:

AN:

248936

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.000715

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000138

AC:

AN:

152400

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.000797

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2022

The c.1742A>G (p.E581G) alteration is located in exon 8 (coding exon 8) of the MCPH1 gene. This alteration results from a A to G substitution at nucleotide position 1742, causing the glutamic acid (E) at amino acid position 581 to be replaced by a glycine (G). The p.E581G 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

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 04, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.0

DANN

Benign

0.96

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.14

M_CAP

Benign

0.0061

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.089

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.88

P;.;.

Vest4

0.10

MVP

0.50

ClinPred

0.022

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.087

gMVP

0.11

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

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