rs35590577

Positions:

chr8-6444585-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024596.5(MCPH1):c.863C>A(p.Pro288His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,614,020 control chromosomes in the GnomAD database, including 1,688 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.067 ( 845 hom., cov: 33)

Exomes 𝑓: 0.017 ( 843 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001151681).

BP6

Variant 8-6444585-C-A is Benign according to our data. Variant chr8-6444585-C-A is described in ClinVar as [Benign]. Clinvar id is 158876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6444585-C-A is described in Lovd as [Benign]. Variant chr8-6444585-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5 linkuse as main transcript	c.863C>A	p.Pro288His	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.863C>A	p.Pro288His	missense_variant	8/14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.0668

AC:

10165

AN:

152086

Hom.:

842

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0369

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0126

Gnomad OTH

AF:

0.0660

GnomAD3 exomes

AF:

0.0267

AC:

6655

AN:

249290

Hom.:

365

AF XY:

0.0233

AC XY:

3154

AN XY:

135258

show subpopulations

Gnomad AFR exome

AF:

0.200

Gnomad AMR exome

AF:

0.0206

Gnomad ASJ exome

AF:

0.0193

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0105

Gnomad FIN exome

AF:

0.0356

Gnomad NFE exome

AF:

0.0128

Gnomad OTH exome

AF:

0.0198

GnomAD4 exome

AF:

0.0170

AC:

24898

AN:

1461816

Hom.:

843

Cov.:

AF XY:

0.0163

AC XY:

11849

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.196

Gnomad4 AMR exome

AF:

0.0217

Gnomad4 ASJ exome

AF:

0.0192

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0107

Gnomad4 FIN exome

AF:

0.0343

Gnomad4 NFE exome

AF:

0.0110

Gnomad4 OTH exome

AF:

0.0259

GnomAD4 genome

AF:

0.0669

AC:

10180

AN:

152204

Hom.:

845

Cov.:

AF XY:

0.0660

AC XY:

4914

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.195

Gnomad4 AMR

AF:

0.0368

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0101

Gnomad4 FIN

AF:

0.0386

Gnomad4 NFE

AF:

0.0126

Gnomad4 OTH

AF:

0.0653

Alfa

AF:

0.0240

Hom.:

283

Bravo

AF:

0.0722

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.186

AC:

680

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.0288

AC:

3481

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Microcephaly 1, primary, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.00096

FATHMM_MKL

Benign

0.39

MetaRNN

Benign

0.0012

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Benign

0.10

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.051

T;D;T

Polyphen

1.0

D;.;.

Vest4

0.13

ClinPred

0.019

GERP RS

4.4

Varity_R

0.18

gMVP

0.34

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