rs2912016

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024596.5(MCPH1):c.2418C>A(p.Ala806=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,613,730 control chromosomes in the GnomAD database, including 106,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10740 hom., cov: 33)

Exomes 𝑓: 0.36 ( 95947 hom. )

Consequence

MCPH1
NM_024596.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.28

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 made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-6621657-C-A is Benign according to our data. Variant chr8-6621657-C-A is described in ClinVar as [Benign]. Clinvar id is 158857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6621657-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.28 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5 linkuse as main transcript	c.2418C>A	p.Ala806=	synonymous_variant	13/14	ENST00000344683.10	NP_078872.3
MCPH1-AS1	NR_125386.1 linkuse as main transcript	n.230-22G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 linkuse as main transcript	c.2418C>A	p.Ala806=	synonymous_variant	13/14	1	NM_024596.5	ENSP00000342924	P1	Q8NEM0-1
MCPH1-AS1	ENST00000661193.1 linkuse as main transcript	n.1055-1433G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.375

AC:

56918

AN:

151976

Hom.:

10722

Cov.:

show subpopulations

Gnomad AFR

AF:

0.421

Gnomad AMI

AF:

0.272

Gnomad AMR

AF:

0.336

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.430

Gnomad SAS

AF:

0.415

Gnomad FIN

AF:

0.368

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.370

GnomAD3 exomes

AF:

0.364

AC:

90860

AN:

249360

Hom.:

16812

AF XY:

0.367

AC XY:

49625

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.425

Gnomad AMR exome

AF:

0.318

Gnomad ASJ exome

AF:

0.303

Gnomad EAS exome

AF:

0.426

Gnomad SAS exome

AF:

0.421

Gnomad FIN exome

AF:

0.366

Gnomad NFE exome

AF:

0.351

Gnomad OTH exome

AF:

0.350

GnomAD4 exome

AF:

0.361

AC:

527805

AN:

1461636

Hom.:

95947

Cov.:

AF XY:

0.363

AC XY:

263955

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.428

Gnomad4 AMR exome

AF:

0.319

Gnomad4 ASJ exome

AF:

0.301

Gnomad4 EAS exome

AF:

0.447

Gnomad4 SAS exome

AF:

0.427

Gnomad4 FIN exome

AF:

0.372

Gnomad4 NFE exome

AF:

0.353

Gnomad4 OTH exome

AF:

0.359

GnomAD4 genome

AF:

0.375

AC:

56973

AN:

152094

Hom.:

10740

Cov.:

AF XY:

0.377

AC XY:

28055

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.421

Gnomad4 AMR

AF:

0.336

Gnomad4 ASJ

AF:

0.307

Gnomad4 EAS

AF:

0.430

Gnomad4 SAS

AF:

0.415

Gnomad4 FIN

AF:

0.368

Gnomad4 NFE

AF:

0.354

Gnomad4 OTH

AF:

0.369

Alfa

AF:

0.348

Hom.:

12123

Bravo

AF:

0.373

Asia WGS

AF:

0.387

AC:

1344

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -

Microcephaly 1, primary, autosomal recessive

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.034

DANN

Benign

0.64

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over