8-6436159-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_024596.5(MCPH1):c.433C>T(p.Leu145Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,612,672 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

MCPH1
NM_024596.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.0170

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

microcephaly 1, primary, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
microcephaly with intellectual disability
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MCPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 8-6436159-C-T is Benign according to our data. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285. Variant chr8-6436159-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 167285.

BP7

Synonymous conserved (PhyloP=0.017 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.433C>T	p.Leu145Leu	synonymous_variant	Exon 5 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.433C>T	p.Leu145Leu	synonymous_variant	Exon 5 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

227

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00237

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00129

AC:

321

AN:

249014

AF XY:

0.00121

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00232

GnomAD4 exome

AF:

0.00188

AC:

2740

AN:

1460352

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1283

AN XY:

726480

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33436

American (AMR)

AF:

0.00195

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39622

South Asian (SAS)

AF:

0.00

AC:

AN:

86094

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5440

European-Non Finnish (NFE)

AF:

0.00226

AC:

2508

AN:

1111372

Other (OTH)

AF:

0.00216

AC:

130

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

129

257

386

514

643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00149

AC:

227

AN:

152320

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41584

American (AMR)

AF:

0.00261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00237

AC:

161

AN:

68026

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000975

Hom.:

Bravo

AF:

0.00156

EpiCase

AF:

0.00229

EpiControl

AF:

0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Oct 01, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MCPH1: BP4, BP7 -

not specified

Benign:2

Jul 01, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 16, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 1, primary, autosomal recessive

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

MCPH1-related disorder

Benign:1

Mar 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.1

(source)

DANN

Benign

0.57

PhyloP100

0.017

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over