rs1057091

chr8-6643023-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024596.5(MCPH1):c.2482C>T(p.Pro828Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,612,652 control chromosomes in the GnomAD database, including 75,303 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. P828P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5685 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69618 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.293

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002649963).
• BP6: Variant 8-6643023-C-T is Benign according to our data. Variant chr8-6643023-C-T is described in ClinVar as [Benign]. Clinvar id is 21703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6643023-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.2482C>T	p.Pro828Ser	missense_variant	14/14	ENST00000344683.10
MCPH1-AS1	NR_125386.1	n.70-15713G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.2482C>T	p.Pro828Ser	missense_variant	14/14	1	NM_024596.5	P1
MCPH1-AS1	ENST00000661193.1	n.70-7604G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40440 AN: 151942 Hom.: 5678 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.277

GnomAD3 exomes AF: 0.285 AC: 71022 AN: 249044 Hom.: 10691 AF XY: 0.295 AC XY: 39829 AN XY: 135096

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.203

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.306 AC: 447083 AN: 1460592 Hom.: 69618 Cov.: 34 AF XY: 0.310 AC XY: 224911 AN XY: 726664

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome AF: 0.266 AC: 40477 AN: 152060 Hom.: 5685 Cov.: 32 AF XY: 0.268 AC XY: 19896 AN XY: 74312

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.314

Gnomad4 OTH AF: 0.277

Alfa AF: 0.305 Hom.: 17582

Bravo AF: 0.255

TwinsUK AF: 0.288 AC: 1067

ALSPAC AF: 0.308 AC: 1188

ESP6500AA AF: 0.186 AC: 730

ESP6500EA AF: 0.302 AC: 2508

ExAC AF: 0.292 AC: 35252

Asia WGS AF: 0.292 AC: 1016 AN: 3478

EpiCase AF: 0.310

EpiControl AF: 0.311

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive Benign:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -
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	Illumina Laboratory Services, Illumina	Jan 13, 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2015	- -
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	Athena Diagnostics	Aug 02, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	3.5
Dann	Benign	0.74
DEOGEN2	Benign	0.055	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00036	N
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.51	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.17
Sift	Benign	0.41	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.017
ClinPred		0.00018	T
GERP RS		-1.4
Varity_R		0.096
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1057091; hg19: chr8-6500544; COSMIC: COSV60913742;