8-6444633-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024596.5(MCPH1):c.911G>T(p.Arg304Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,613,798 control chromosomes in the GnomAD database, including 16,233 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1092 hom., cov: 33)

Exomes 𝑓: 0.14 ( 15141 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.646

Publications

32 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.748174E-4).

BP6

Variant 8-6444633-G-T is Benign according to our data. Variant chr8-6444633-G-T is described in ClinVar as Benign. ClinVar VariationId is 158879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.911G>T	p.Arg304Ile	missense_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.911G>T	p.Arg304Ile	missense_variant	Exon 8 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16249

AN:

152092

Hom.:

1092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0425

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.0999

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.0210

Gnomad SAS

AF:

0.0873

Gnomad FIN

AF:

0.0679

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.153

Gnomad OTH

AF:

0.128

GnomAD2 exomes

AF:

0.113

AC:

28259

AN:

249024

AF XY:

0.116

show subpopulations

Gnomad AFR exome

AF:

0.0355

Gnomad AMR exome

AF:

0.0673

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.0174

Gnomad FIN exome

AF:

0.0646

Gnomad NFE exome

AF:

0.155

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.139

AC:

202430

AN:

1461584

Hom.:

15141

Cov.:

AF XY:

0.138

AC XY:

100356

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.0379

AC:

1269

AN:

33478

American (AMR)

AF:

0.0725

AC:

3244

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

7095

AN:

26134

East Asian (EAS)

AF:

0.0331

AC:

1315

AN:

39700

South Asian (SAS)

AF:

0.0871

AC:

7516

AN:

86256

European-Finnish (FIN)

AF:

0.0692

AC:

3680

AN:

53192

Middle Eastern (MID)

AF:

0.235

AC:

1355

AN:

5768

European-Non Finnish (NFE)

AF:

0.152

AC:

168566

AN:

1111942

Other (OTH)

AF:

0.139

AC:

8390

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

10782

21564

32346

43128

53910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5864

11728

17592

23456

29320

<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:

0.107

AC:

16245

AN:

152214

Hom.:

1092

Cov.:

AF XY:

0.101

AC XY:

7528

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0423

AC:

1759

AN:

41544

American (AMR)

AF:

0.0997

AC:

1526

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

893

AN:

3464

East Asian (EAS)

AF:

0.0208

AC:

108

AN:

5192

South Asian (SAS)

AF:

0.0871

AC:

420

AN:

4820

European-Finnish (FIN)

AF:

0.0679

AC:

718

AN:

10578

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.153

AC:

10390

AN:

67994

Other (OTH)

AF:

0.126

AC:

267

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

746

1493

2239

2986

3732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.142

Hom.:

6832

Bravo

AF:

0.106

TwinsUK

AF:

0.159

AC:

588

ALSPAC

AF:

0.153

AC:

589

ESP6500AA

AF:

0.0397

AC:

147

ESP6500EA

AF:

0.154

AC:

1256

ExAC

AF:

0.115

AC:

13897

Asia WGS

AF:

0.0560

AC:

195

AN:

3478

EpiCase

AF:

0.167

EpiControl

AF:

0.166

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 1, primary, autosomal recessive

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 28, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.18

T;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.075

MetaRNN

Benign

0.00087

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;M;.

PhyloP100

-0.65

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.049

Sift

Uncertain

0.0080

D;D;D

Sift4G

Benign

0.090

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.077

ClinPred

0.030

GERP RS

-2.2

Varity_R

0.14

gMVP

0.17

Mutation Taster

=99/1

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