rs930557

chr8-6444662-G-Cchr8-6444662-G-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.940G>C(p.Asp314His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,834 control chromosomes in the GnomAD database, including 511,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D314D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.68 (38517 hom., cov: 33)
  • Exomes 𝑓: 0.80 (473061 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.257

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.8958876E-7).
• BP6: Variant 8-6444662-G-C is Benign according to our data. Variant chr8-6444662-G-C is described in ClinVar as [Benign]. Clinvar id is 21705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6444662-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.940G>C	p.Asp314His	missense_variant	8/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.940G>C	p.Asp314His	missense_variant	8/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103254 AN: 152040 Hom.: 38511 Cov.: 33

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.787

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.690

GnomAD3 exomes AF: 0.781 AC: 194302 AN: 248836 Hom.: 77930 AF XY: 0.784 AC XY: 105989 AN XY: 135108

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.790

Gnomad SAS exome AF: 0.755

Gnomad FIN exome AF: 0.887

Gnomad NFE exome AF: 0.813

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.800 AC: 1169787 AN: 1461676 Hom.: 473061 Cov.: 62 AF XY: 0.800 AC XY: 581625 AN XY: 727120

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.849

Gnomad4 ASJ exome AF: 0.688

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.755

Gnomad4 FIN exome AF: 0.884

Gnomad4 NFE exome AF: 0.818

Gnomad4 OTH exome AF: 0.766

GnomAD4 genome AF: 0.679 AC: 103273 AN: 152158 Hom.: 38517 Cov.: 33 AF XY: 0.687 AC XY: 51099 AN XY: 74414

Gnomad4 AFR AF: 0.336

Gnomad4 AMR AF: 0.790

Gnomad4 ASJ AF: 0.700

Gnomad4 EAS AF: 0.788

Gnomad4 SAS AF: 0.747

Gnomad4 FIN AF: 0.880

Gnomad4 NFE AF: 0.815

Gnomad4 OTH AF: 0.692

Alfa AF: 0.785 Hom.: 35884

Bravo AF: 0.659

TwinsUK AF: 0.809 AC: 2998

ALSPAC AF: 0.811 AC: 3126

ESP6500AA AF: 0.374 AC: 1404

ESP6500EA AF: 0.814 AC: 6685

ExAC AF: 0.770 AC: 93070

Asia WGS AF: 0.745 AC: 2587 AN: 3478

EpiCase AF: 0.796

EpiControl AF: 0.798

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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. -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
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	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	8.9e-7	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N;D;N
REVEL	Benign	0.085
Sift	Benign	0.056	T;D;D
Sift4G	Uncertain	0.030	D;T;T
Polyphen		1.0	D;.;.
Vest4		0.051
ClinPred		0.020	T
GERP RS		2.7
Varity_R		0.082
gMVP		0.22

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

Other links and lift over

dbSNP: rs930557; hg19: chr8-6302183; COSMIC: COSV60915866;