rs11137040

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.2215-15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,606,776 control chromosomes in the GnomAD database, including 64,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5265 hom., cov: 33)

Exomes 𝑓: 0.28 ( 59324 hom. )

Consequence

MCPH1
NM_024596.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.593

Publications

9 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 links:

MCPH1-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

MCPH1-AS1 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 (BayesDel_noAF=-0.85).

BP6

Variant 8-6621439-C-G is Benign according to our data. Variant chr8-6621439-C-G is described in ClinVar as [Benign]. Clinvar id is 158842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.2215-15C>G		intron_variant	Intron 12 of 13	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.2215-15C>G		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39445

AN:

151950

Hom.:

5258

Cov.:

show subpopulations

Gnomad AFR

AF:

0.258

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.188

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.0742

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.259

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.259

GnomAD2 exomes

AF:

0.243

AC:

60373

AN:

248108

AF XY:

0.250

show subpopulations

Gnomad AFR exome

AF:

0.254

Gnomad AMR exome

AF:

0.152

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.0625

Gnomad FIN exome

AF:

0.264

Gnomad NFE exome

AF:

0.288

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.281

AC:

408159

AN:

1454708

Hom.:

59324

Cov.:

AF XY:

0.281

AC XY:

203163

AN XY:

723968

show subpopulations

African (AFR)

AF:

0.260

AC:

8693

AN:

33382

American (AMR)

AF:

0.157

AC:

7013

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

5788

AN:

26090

East Asian (EAS)

AF:

0.119

AC:

4740

AN:

39700

South Asian (SAS)

AF:

0.279

AC:

23998

AN:

86168

European-Finnish (FIN)

AF:

0.273

AC:

14434

AN:

52950

Middle Eastern (MID)

AF:

0.330

AC:

1900

AN:

5764

European-Non Finnish (NFE)

AF:

0.295

AC:

325651

AN:

1105750

Other (OTH)

AF:

0.265

AC:

15942

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

14815

29630

44446

59261

74076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.260

AC:

39482

AN:

152068

Hom.:

5265

Cov.:

AF XY:

0.256

AC XY:

19004

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.259

AC:

10720

AN:

41466

American (AMR)

AF:

0.187

AC:

2865

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

798

AN:

3472

East Asian (EAS)

AF:

0.0742

AC:

384

AN:

5174

South Asian (SAS)

AF:

0.254

AC:

1222

AN:

4820

European-Finnish (FIN)

AF:

0.259

AC:

2737

AN:

10578

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.293

AC:

19922

AN:

67952

Other (OTH)

AF:

0.258

AC:

545

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1490

2979

4469

5958

7448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.194

Hom.:

583

Bravo

AF:

0.253

Asia WGS

AF:

0.173

AC:

604

AN:

3478

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

- -

Apr 10, 2014

Eurofins Ntd Llc (ga)

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

- -

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

- -

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

1.4

(source)

DANN

Benign

0.64

PhyloP100

-0.59

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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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rs11137040

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