8-6409253-G-A

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.23-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,569,786 control chromosomes in the GnomAD database, including 51,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 10445 hom., cov: 32)

Exomes 𝑓: 0.23 ( 40994 hom. )

Consequence

MCPH1
NM_024596.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.36

Publications

8 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 (BayesDel_noAF=-0.8).

BP6

Variant 8-6409253-G-A is Benign according to our data. Variant chr8-6409253-G-A is described in ClinVar as Benign. ClinVar VariationId is 158854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCPH1	NM_024596.5	MANE Select	c.23-26G>A	intron	N/A	NP_078872.3
MCPH1	NM_001322042.2		c.23-26G>A	intron	N/A	NP_001308971.2
MCPH1	NM_001410917.1		c.23-26G>A	intron	N/A	NP_001397846.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.23-26G>A	intron	N/A	ENSP00000342924.5
MCPH1	ENST00000519480.6	TSL:1	c.23-26G>A	intron	N/A	ENSP00000430962.1
MCPH1	ENST00000692836.1		c.23-26G>A	intron	N/A	ENSP00000509971.1

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49785

AN:

151902

Hom.:

10413

Cov.:

show subpopulations

Gnomad AFR

AF:

0.602

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.269

Gnomad ASJ

AF:

0.315

Gnomad EAS

AF:

0.305

Gnomad SAS

AF:

0.275

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.215

Gnomad OTH

AF:

0.311

GnomAD2 exomes

AF:

0.251

AC:

62496

AN:

249246

AF XY:

0.246

show subpopulations

Gnomad AFR exome

AF:

0.614

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.322

Gnomad EAS exome

AF:

0.304

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.216

Gnomad OTH exome

AF:

0.240

GnomAD4 exome

AF:

0.230

AC:

325397

AN:

1417766

Hom.:

40994

Cov.:

AF XY:

0.230

AC XY:

162640

AN XY:

708232

show subpopulations

African (AFR)

AF:

0.619

AC:

20185

AN:

32610

American (AMR)

AF:

0.226

AC:

10073

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.324

AC:

8386

AN:

25854

East Asian (EAS)

AF:

0.292

AC:

11516

AN:

39480

South Asian (SAS)

AF:

0.265

AC:

22639

AN:

85322

European-Finnish (FIN)

AF:

0.123

AC:

6541

AN:

53352

Middle Eastern (MID)

AF:

0.366

AC:

2088

AN:

5702

European-Non Finnish (NFE)

AF:

0.213

AC:

228678

AN:

1071830

Other (OTH)

AF:

0.259

AC:

15291

AN:

58962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

11674

23348

35022

46696

58370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8090

16180

24270

32360

40450

<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:

0.328

AC:

49861

AN:

152020

Hom.:

10445

Cov.:

AF XY:

0.321

AC XY:

23876

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.602

AC:

24923

AN:

41390

American (AMR)

AF:

0.268

AC:

4100

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

1092

AN:

3466

East Asian (EAS)

AF:

0.304

AC:

1571

AN:

5166

South Asian (SAS)

AF:

0.275

AC:

1325

AN:

4822

European-Finnish (FIN)

AF:

0.123

AC:

1303

AN:

10582

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.215

AC:

14606

AN:

67998

Other (OTH)

AF:

0.310

AC:

654

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1458

2915

4373

5830

7288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.256

Hom.:

20541

Bravo

AF:

0.349

Asia WGS

AF:

0.297

AC:

1036

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 03, 2018

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

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Microcephaly 1, primary, autosomal recessive

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.81

(source)

DANN

Benign

0.84

PhyloP100

1.4

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over