rs930557

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.940G>C(p.Asp314His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,834 control chromosomes in the GnomAD database, including 511,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D314D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.68 ( 38517 hom., cov: 33)

Exomes 𝑓: 0.80 ( 473061 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.257

Publications

59 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=8.8958876E-7).

BP6

Variant 8-6444662-G-C is Benign according to our data. Variant chr8-6444662-G-C is described in ClinVar as Benign. ClinVar VariationId is 21705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.940G>C	p.Asp314His	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.940G>C	p.Asp314His	missense_variant	Exon 8 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.679

AC:

103254

AN:

152040

Hom.:

38511

Cov.:

show subpopulations

Gnomad AFR

AF:

0.337

Gnomad AMI

AF:

0.853

Gnomad AMR

AF:

0.789

Gnomad ASJ

AF:

0.700

Gnomad EAS

AF:

0.787

Gnomad SAS

AF:

0.746

Gnomad FIN

AF:

0.880

Gnomad MID

AF:

0.646

Gnomad NFE

AF:

0.815

Gnomad OTH

AF:

0.690

GnomAD2 exomes

AF:

0.781

AC:

194302

AN:

248836

AF XY:

0.784

show subpopulations

Gnomad AFR exome

AF:

0.322

Gnomad AMR exome

AF:

0.857

Gnomad ASJ exome

AF:

0.690

Gnomad EAS exome

AF:

0.790

Gnomad FIN exome

AF:

0.887

Gnomad NFE exome

AF:

0.813

Gnomad OTH exome

AF:

0.792

GnomAD4 exome

AF:

0.800

AC:

1169787

AN:

1461676

Hom.:

473061

Cov.:

AF XY:

0.800

AC XY:

581625

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.321

AC:

10744

AN:

33474

American (AMR)

AF:

0.849

AC:

37976

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.688

AC:

17988

AN:

26136

East Asian (EAS)

AF:

0.793

AC:

31461

AN:

39698

South Asian (SAS)

AF:

0.755

AC:

65122

AN:

86248

European-Finnish (FIN)

AF:

0.884

AC:

47131

AN:

53296

Middle Eastern (MID)

AF:

0.666

AC:

3839

AN:

5768

European-Non Finnish (NFE)

AF:

0.818

AC:

909236

AN:

1111940

Other (OTH)

AF:

0.766

AC:

46290

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

13472

26944

40416

53888

67360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20836

41672

62508

83344

104180

<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:

0.679

AC:

103273

AN:

152158

Hom.:

38517

Cov.:

AF XY:

0.687

AC XY:

51099

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.336

AC:

13933

AN:

41458

American (AMR)

AF:

0.790

AC:

12079

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.700

AC:

2430

AN:

3470

East Asian (EAS)

AF:

0.788

AC:

4084

AN:

5186

South Asian (SAS)

AF:

0.747

AC:

3601

AN:

4822

European-Finnish (FIN)

AF:

0.880

AC:

9336

AN:

10606

Middle Eastern (MID)

AF:

0.616

AC:

181

AN:

294

European-Non Finnish (NFE)

AF:

0.815

AC:

55392

AN:

68006

Other (OTH)

AF:

0.692

AC:

1459

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1385

2770

4155

5540

6925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.785

Hom.:

35884

Bravo

AF:

0.659

TwinsUK

AF:

0.809

AC:

2998

ALSPAC

AF:

0.811

AC:

3126

ESP6500AA

AF:

0.374

AC:

1404

ESP6500EA

AF:

0.814

AC:

6685

ExAC

AF:

0.770

AC:

93070

Asia WGS

AF:

0.745

AC:

2587

AN:

3478

EpiCase

AF:

0.796

EpiControl

AF:

0.798

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive

Benign:4Other: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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

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

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:3

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;.;.

Eigen

Benign

-0.080

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.17

MetaRNN

Benign

8.9e-7

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

0.26

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.3

N;D;N

REVEL

Benign

0.085

Sift

Benign

0.056

T;D;D

Sift4G

Uncertain

0.030

D;T;T

Polyphen

1.0

D;.;.

Vest4

0.051

ClinPred

0.020

GERP RS

2.7

Varity_R

0.082

gMVP

0.22

Mutation Taster

=98/2

polymorphism (auto)

(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