8-6643023-C-T

Position:

chr8-6643023-C-T

Variant summary

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

The NM_024596.5(MCPH1):c.2482C>T(p.Pro828Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,612,652 control chromosomes in the GnomAD database, including 75,303 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5685 hom., cov: 32)

Exomes 𝑓: 0.31 ( 69618 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.293

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=0.002649963).

BP6

Variant 8-6643023-C-T is Benign according to our data. Variant chr8-6643023-C-T is described in ClinVar as [Benign]. Clinvar id is 21703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6643023-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.374 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.2482C>T	p.Pro828Ser	missense_variant	14/14	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.2482C>T	p.Pro828Ser	missense_variant	14/14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.266

AC:

40440

AN:

151942

Hom.:

5678

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.290

Gnomad AMR

AF:

0.205

Gnomad ASJ

AF:

0.318

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.388

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.314

Gnomad OTH

AF:

0.277

GnomAD3 exomes

AF:

0.285

AC:

71022

AN:

249044

Hom.:

10691

AF XY:

0.295

AC XY:

39829

AN XY:

135096

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.203

Gnomad SAS exome

AF:

0.387

Gnomad FIN exome

AF:

0.284

Gnomad NFE exome

AF:

0.312

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.306

AC:

447083

AN:

1460592

Hom.:

69618

Cov.:

AF XY:

0.310

AC XY:

224911

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.191

Gnomad4 AMR exome

AF:

0.195

Gnomad4 ASJ exome

AF:

0.308

Gnomad4 EAS exome

AF:

0.272

Gnomad4 SAS exome

AF:

0.393

Gnomad4 FIN exome

AF:

0.293

Gnomad4 NFE exome

AF:

0.310

Gnomad4 OTH exome

AF:

0.296

GnomAD4 genome

AF:

0.266

AC:

40477

AN:

152060

Hom.:

5685

Cov.:

AF XY:

0.268

AC XY:

19896

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.193

Gnomad4 AMR

AF:

0.205

Gnomad4 ASJ

AF:

0.318

Gnomad4 EAS

AF:

0.222

Gnomad4 SAS

AF:

0.389

Gnomad4 FIN

AF:

0.280

Gnomad4 NFE

AF:

0.314

Gnomad4 OTH

AF:

0.277

Alfa

AF:

0.305

Hom.:

17582

Bravo

AF:

0.255

TwinsUK

AF:

0.288

AC:

1067

ALSPAC

AF:

0.308

AC:

1188

ESP6500AA

AF:

0.186

AC:

730

ESP6500EA

AF:

0.302

AC:

2508

ExAC

AF:

0.292

AC:

35252

Asia WGS

AF:

0.292

AC:

1016

AN:

3478

EpiCase

AF:

0.310

EpiControl

AF:

0.311

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive

Benign:5Other:1

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -

not provided

Benign:3

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

3.5

DANN

Benign

0.74

DEOGEN2

Benign

0.055

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00036

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.51

PrimateAI

Benign

0.28

PROVEAN

Benign

0.63

REVEL

Benign

0.17

Sift

Benign

0.41

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.017

ClinPred

0.00018

GERP RS

-1.4

Varity_R

0.096

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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