8-6621521-C-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.2282C>T(p.Ala761Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 1,613,234 control chromosomes in the GnomAD database, including 143,781 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14463 hom., cov: 33)

Exomes 𝑓: 0.42 ( 129318 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -0.503

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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

MCPH1-AS1 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=3.4113652E-6).

BP6

Variant 8-6621521-C-T is Benign according to our data. Variant chr8-6621521-C-T is described in ClinVar as [Benign]. Clinvar id is 21702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6621521-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.2282C>T	p.Ala761Val	missense_variant	Exon 13 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.2282C>T	p.Ala761Val	missense_variant	Exon 13 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.432

AC:

65663

AN:

151916

Hom.:

14441

Cov.:

show subpopulations

Gnomad AFR

AF:

0.470

Gnomad AMI

AF:

0.326

Gnomad AMR

AF:

0.392

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.672

Gnomad SAS

AF:

0.494

Gnomad FIN

AF:

0.408

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.406

Gnomad OTH

AF:

0.432

GnomAD3 exomes

AF:

0.433

AC:

108048

AN:

249372

Hom.:

24189

AF XY:

0.434

AC XY:

58670

AN XY:

135302

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.398

Gnomad ASJ exome

AF:

0.339

Gnomad EAS exome

AF:

0.662

Gnomad SAS exome

AF:

0.490

Gnomad FIN exome

AF:

0.410

Gnomad NFE exome

AF:

0.401

Gnomad OTH exome

AF:

0.407

GnomAD4 exome

AF:

0.417

AC:

609561

AN:

1461200

Hom.:

129318

Cov.:

AF XY:

0.419

AC XY:

304878

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.477

Gnomad4 AMR exome

AF:

0.397

Gnomad4 ASJ exome

AF:

0.336

Gnomad4 EAS exome

AF:

0.676

Gnomad4 SAS exome

AF:

0.496

Gnomad4 FIN exome

AF:

0.417

Gnomad4 NFE exome

AF:

0.403

Gnomad4 OTH exome

AF:

0.416

GnomAD4 genome

AF:

0.432

AC:

65728

AN:

152034

Hom.:

14463

Cov.:

AF XY:

0.436

AC XY:

32366

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.470

Gnomad4 AMR

AF:

0.393

Gnomad4 ASJ

AF:

0.343

Gnomad4 EAS

AF:

0.672

Gnomad4 SAS

AF:

0.494

Gnomad4 FIN

AF:

0.408

Gnomad4 NFE

AF:

0.406

Gnomad4 OTH

AF:

0.431

Alfa

AF:

0.406

Hom.:

29897

Bravo

AF:

0.433

TwinsUK

AF:

0.382

AC:

1416

ALSPAC

AF:

0.394

AC:

1517

ESP6500AA

AF:

0.444

AC:

1888

ESP6500EA

AF:

0.392

AC:

3316

ExAC

AF:

0.436

AC:

52750

Asia WGS

AF:

0.530

AC:

1846

AN:

3478

EpiCase

AF:

0.399

EpiControl

AF:

0.395

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive

Benign:4Other:1

Sep 21, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified

Benign:4

Apr 10, 2014

Eurofins Ntd Llc (ga)

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

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18204051) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.18

DANN

Benign

0.70

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0056

MetaRNN

Benign

0.0000034

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.91

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.011

ClinPred

0.0058

GERP RS

-8.3

Varity_R

0.031

gMVP

0.26

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