dbSNP rs111713406: MCPH1:c.2453-13G>A (chr8-6642981-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024596.5(MCPH1):c.2453-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,612,774 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00074 ( 18 hom. )

Consequence

MCPH1
NM_024596.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.311

Publications

2 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=-0.86).

BP6

Variant 8-6642981-G-A is Benign according to our data. Variant chr8-6642981-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00694 (1055/152080) while in subpopulation AFR AF = 0.0242 (1004/41478). AF 95% confidence interval is 0.023. There are 15 homozygotes in GnomAd4. There are 476 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

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.2453-13G>A	intron	N/A	NP_078872.3
MCPH1	NM_001322042.2		c.2595-13G>A	intron	N/A	NP_001308971.2
MCPH1	NM_001363980.2		c.2174-13G>A	intron	N/A	NP_001350909.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2453-13G>A	intron	N/A	ENSP00000342924.5
MCPH1	ENST00000689348.1		c.2595-13G>A	intron	N/A	ENSP00000509554.1
MCPH1	ENST00000689633.1		c.2174-13G>A	intron	N/A	ENSP00000509054.1

Frequencies

GnomAD3 genomes

AF:

0.00690

AC:

1048

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00183

AC:

455

AN:

249204

AF XY:

0.00135

show subpopulations

Gnomad AFR exome

AF:

0.0249

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000745

AC:

1088

AN:

1460694

Hom.:

Cov.:

AF XY:

0.000661

AC XY:

480

AN XY:

726712

show subpopulations

African (AFR)

AF:

0.0253

AC:

846

AN:

33390

American (AMR)

AF:

0.00197

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000220

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1111130

Other (OTH)

AF:

0.00187

AC:

113

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

112

168

224

280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00694

AC:

1055

AN:

152080

Hom.:

Cov.:

AF XY:

0.00640

AC XY:

476

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0242

AC:

1004

AN:

41478

American (AMR)

AF:

0.00255

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

165

220

275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00404

Hom.:

Bravo

AF:

0.00781

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.5

(source)

DANN

Benign

0.64

PhyloP100

-0.31

Mutation Taster

=100/0

polymorphism

(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

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