rs2920676

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

11 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 -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 VariationId is 96128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

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

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

GnomAD2 exomes

AF:

0.0795

AC:

19828

AN:

249454

AF XY:

0.0761

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 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

African (AFR)

AF:

0.424

AC:

14190

AN:

33478

American (AMR)

AF:

0.0618

AC:

2764

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

948

AN:

26136

East Asian (EAS)

AF:

0.155

AC:

6160

AN:

39700

South Asian (SAS)

AF:

0.149

AC:

12849

AN:

86258

European-Finnish (FIN)

AF:

0.0353

AC:

1888

AN:

53414

Middle Eastern (MID)

AF:

0.0756

AC:

436

AN:

5768

European-Non Finnish (NFE)

AF:

0.0168

AC:

18633

AN:

1112010

Other (OTH)

AF:

0.0666

AC:

4021

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3553

7106

10658

14211

17764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1094

2188

3282

4376

5470

<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:

0.144

AC:

21911

AN:

152242

Hom.:

3760

Cov.:

AF XY:

0.143

AC XY:

10633

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.409

AC:

16975

AN:

41492

American (AMR)

AF:

0.0812

AC:

1242

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0377

AC:

131

AN:

3472

East Asian (EAS)

AF:

0.161

AC:

831

AN:

5174

South Asian (SAS)

AF:

0.157

AC:

757

AN:

4830

European-Finnish (FIN)

AF:

0.0392

AC:

416

AN:

10614

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0185

AC:

1261

AN:

68038

Other (OTH)

AF:

0.130

AC:

274

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

729

1459

2188

2918

3647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.0661

Hom.:

2209

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

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

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

- -

Dec 20, 2014

Eurofins Ntd Llc (ga)

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

-0.85

CADD

Benign

0.63

(source)

DANN

Benign

0.40

PhyloP100

-0.90

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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