Genetic Variant NM_024596.5:c.1428C>T (chr8-6445150-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The NM_024596.5(MCPH1):c.1428C>T(p.Phe476Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,614,124 control chromosomes in the GnomAD database, including 8,961 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 3760 hom., cov: 33)

Exomes 𝑓: 0.042 ( 5201 hom. )

Consequence

MCPH1
NM_024596.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.895

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=-0.85).

BP6

Variant 8-6445150-C-T is Benign according to our data. Variant chr8-6445150-C-T is described in ClinVar as [Benign]. Clinvar id is 96128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6445150-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.895 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.1428C>T	p.Phe476Phe	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.1428C>T	p.Phe476Phe	synonymous_variant	Exon 8 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.144

AC:

21858

AN:

152124

Hom.:

3747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.409

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0814

Gnomad ASJ

AF:

0.0377

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.0392

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.130

GnomAD3 exomes

AF:

0.0795

AC:

19828

AN:

249454

Hom.:

2173

AF XY:

0.0761

AC XY:

10298

AN XY:

135350

show subpopulations

Gnomad AFR exome

AF:

0.430

Gnomad AMR exome

AF:

0.0610

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.157

Gnomad SAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.0365

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0488

GnomAD4 exome

AF:

0.0423

AC:

61889

AN:

1461882

Hom.:

5201

Cov.:

AF XY:

0.0440

AC XY:

32006

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.424

Gnomad4 AMR exome

AF:

0.0618

Gnomad4 ASJ exome

AF:

0.0363

Gnomad4 EAS exome

AF:

0.155

Gnomad4 SAS exome

AF:

0.149

Gnomad4 FIN exome

AF:

0.0353

Gnomad4 NFE exome

AF:

0.0168

Gnomad4 OTH exome

AF:

0.0666

GnomAD4 genome

AF:

0.144

AC:

21911

AN:

152242

Hom.:

3760

Cov.:

AF XY:

0.143

AC XY:

10633

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.409

Gnomad4 AMR

AF:

0.0812

Gnomad4 ASJ

AF:

0.0377

Gnomad4 EAS

AF:

0.161

Gnomad4 SAS

AF:

0.157

Gnomad4 FIN

AF:

0.0392

Gnomad4 NFE

AF:

0.0185

Gnomad4 OTH

AF:

0.130

Alfa

AF:

0.0558

Hom.:

1467

Bravo

AF:

0.158

Asia WGS

AF:

0.166

AC:

578

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Dec 20, 2014

Eurofins Ntd Llc (ga)

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

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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.85

CADD

Benign

0.63

DANN

Benign

0.40

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