rs12674488

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.2045C>A(p.Thr682Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,986 control chromosomes in the GnomAD database, including 19,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. T682T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 1574 hom., cov: 32)

Exomes 𝑓: 0.15 ( 17785 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.11

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=9.829998E-4).

BP6

Variant 8-6480785-C-A is Benign according to our data. Variant chr8-6480785-C-A is described in ClinVar as Benign. ClinVar VariationId is 158834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.2045C>A	p.Thr682Asn	missense_variant	Exon 11 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.2045C>A	p.Thr682Asn	missense_variant	Exon 11 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20642

AN:

152058

Hom.:

1575

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0945

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.0925

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.163

GnomAD2 exomes

AF:

0.149

AC:

37271

AN:

249570

AF XY:

0.153

show subpopulations

Gnomad AFR exome

AF:

0.0915

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.253

Gnomad EAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.0853

Gnomad NFE exome

AF:

0.162

Gnomad OTH exome

AF:

0.161

GnomAD4 exome

AF:

0.153

AC:

223987

AN:

1461810

Hom.:

17785

Cov.:

AF XY:

0.155

AC XY:

112624

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0930

AC:

3112

AN:

33480

American (AMR)

AF:

0.106

AC:

4756

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

6659

AN:

26136

East Asian (EAS)

AF:

0.183

AC:

7263

AN:

39700

South Asian (SAS)

AF:

0.183

AC:

15807

AN:

86258

European-Finnish (FIN)

AF:

0.0888

AC:

4744

AN:

53412

Middle Eastern (MID)

AF:

0.241

AC:

1389

AN:

5766

European-Non Finnish (NFE)

AF:

0.153

AC:

170444

AN:

1111946

Other (OTH)

AF:

0.162

AC:

9813

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

11028

22057

33085

44114

55142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6042

12084

18126

24168

30210

<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:

0.136

AC:

20645

AN:

152176

Hom.:

1574

Cov.:

AF XY:

0.133

AC XY:

9893

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0944

AC:

3918

AN:

41512

American (AMR)

AF:

0.128

AC:

1960

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

821

AN:

3468

East Asian (EAS)

AF:

0.170

AC:

876

AN:

5168

South Asian (SAS)

AF:

0.188

AC:

908

AN:

4820

European-Finnish (FIN)

AF:

0.0925

AC:

980

AN:

10596

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.157

AC:

10654

AN:

67996

Other (OTH)

AF:

0.161

AC:

340

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

909

1818

2728

3637

4546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<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:

0.154

Hom.:

6932

Bravo

AF:

0.134

TwinsUK

AF:

0.154

AC:

570

ALSPAC

AF:

0.158

AC:

609

ESP6500AA

AF:

0.0843

AC:

335

ESP6500EA

AF:

0.156

AC:

1301

ExAC

AF:

0.152

AC:

18389

Asia WGS

AF:

0.163

AC:

569

AN:

3478

EpiCase

AF:

0.168

EpiControl

AF:

0.175

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance: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

- -

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

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

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

- -

Feb 02, 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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.52

MetaRNN

Benign

0.00098

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

REVEL

Benign

0.15

Sift

Benign

0.094

Sift4G

Uncertain

0.020

Polyphen

0.98

Vest4

0.086

ClinPred

0.021

GERP RS

0.67

Varity_R

0.16

gMVP

0.23

Mutation Taster

=97/3

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