rs2584

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024596.5(MCPH1):c.1782G>A(p.Thr594Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,610,700 control chromosomes in the GnomAD database, including 81,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5542 hom., cov: 34)

Exomes 𝑓: 0.31 ( 75794 hom. )

Consequence

MCPH1
NM_024596.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.75

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 8-6445504-G-A is Benign according to our data. Variant chr8-6445504-G-A is described in ClinVar as [Benign]. Clinvar id is 158827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6445504-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.1782G>A	p.Thr594Thr	synonymous_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.1782G>A	p.Thr594Thr	synonymous_variant	Exon 8 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.237

AC:

36021

AN:

152082

Hom.:

5542

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0615

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.261

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.0264

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.357

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.217

GnomAD3 exomes

AF:

0.262

AC:

64266

AN:

245124

Hom.:

10051

AF XY:

0.261

AC XY:

34884

AN XY:

133474

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.281

Gnomad ASJ exome

AF:

0.208

Gnomad EAS exome

AF:

0.0227

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.357

Gnomad NFE exome

AF:

0.342

Gnomad OTH exome

AF:

0.276

GnomAD4 exome

AF:

0.310

AC:

452485

AN:

1458500

Hom.:

75794

Cov.:

AF XY:

0.306

AC XY:

221953

AN XY:

725332

show subpopulations

Gnomad4 AFR exome

AF:

0.0490

Gnomad4 AMR exome

AF:

0.276

Gnomad4 ASJ exome

AF:

0.204

Gnomad4 EAS exome

AF:

0.0310

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.362

Gnomad4 NFE exome

AF:

0.345

Gnomad4 OTH exome

AF:

0.274

GnomAD4 genome

AF:

0.237

AC:

36023

AN:

152200

Hom.:

5542

Cov.:

AF XY:

0.233

AC XY:

17318

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0613

Gnomad4 AMR

AF:

0.261

Gnomad4 ASJ

AF:

0.227

Gnomad4 EAS

AF:

0.0264

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.357

Gnomad4 NFE

AF:

0.344

Gnomad4 OTH

AF:

0.215

Alfa

AF:

0.307

Hom.:

10192

Bravo

AF:

0.225

Asia WGS

AF:

0.0750

AC:

264

AN:

3478

EpiCase

AF:

0.315

EpiControl

AF:

0.317

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Microcephaly 1, primary, autosomal recessive

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.20

DANN

Benign

0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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