8-6444633-G-T

Variant names:

Variant summary

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

The NM_024596.5(MCPH1):c.911G>T(p.Arg304Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,613,798 control chromosomes in the GnomAD database, including 16,233 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1092 hom., cov: 33)

Exomes 𝑓: 0.14 ( 15141 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.646

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:

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=8.748174E-4).

BP6

Variant 8-6444633-G-T is Benign according to our data. Variant chr8-6444633-G-T is described in ClinVar as [Benign]. Clinvar id is 158879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6444633-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.911G>T	p.Arg304Ile	missense_variant	Exon 8 of 14	ENST00000344683.10	NP_078872.3	Q8NEM0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 link	c.911G>T	p.Arg304Ile	missense_variant	Exon 8 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16249

AN:

152092

Hom.:

1092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0425

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.0999

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.0210

Gnomad SAS

AF:

0.0873

Gnomad FIN

AF:

0.0679

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.153

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.113

AC:

28259

AN:

249024

Hom.:

2080

AF XY:

0.116

AC XY:

15740

AN XY:

135174

show subpopulations

Gnomad AFR exome

AF:

0.0355

Gnomad AMR exome

AF:

0.0673

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.0174

Gnomad SAS exome

AF:

0.0863

Gnomad FIN exome

AF:

0.0646

Gnomad NFE exome

AF:

0.155

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.139

AC:

202430

AN:

1461584

Hom.:

15141

Cov.:

AF XY:

0.138

AC XY:

100356

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.0379

Gnomad4 AMR exome

AF:

0.0725

Gnomad4 ASJ exome

AF:

0.271

Gnomad4 EAS exome

AF:

0.0331

Gnomad4 SAS exome

AF:

0.0871

Gnomad4 FIN exome

AF:

0.0692

Gnomad4 NFE exome

AF:

0.152

Gnomad4 OTH exome

AF:

0.139

GnomAD4 genome

AF:

0.107

AC:

16245

AN:

152214

Hom.:

1092

Cov.:

AF XY:

0.101

AC XY:

7528

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0423

Gnomad4 AMR

AF:

0.0997

Gnomad4 ASJ

AF:

0.258

Gnomad4 EAS

AF:

0.0208

Gnomad4 SAS

AF:

0.0871

Gnomad4 FIN

AF:

0.0679

Gnomad4 NFE

AF:

0.153

Gnomad4 OTH

AF:

0.126

Alfa

AF:

0.150

Hom.:

3929

Bravo

AF:

0.106

TwinsUK

AF:

0.159

AC:

588

ALSPAC

AF:

0.153

AC:

589

ESP6500AA

AF:

0.0397

AC:

147

ESP6500EA

AF:

0.154

AC:

1256

ExAC

AF:

0.115

AC:

13897

Asia WGS

AF:

0.0560

AC:

195

AN:

3478

EpiCase

AF:

0.167

EpiControl

AF:

0.166

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Microcephaly 1, primary, autosomal recessive

Benign:3

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.18

T;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.075

MetaRNN

Benign

0.00087

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;M;.

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.049

Sift

Uncertain

0.0080

D;D;D

Sift4G

Benign

0.090

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.077

ClinPred

0.030

GERP RS

-2.2

Varity_R

0.14

gMVP

0.17

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