rs2920676

chr8-6445150-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024596.5(MCPH1):c.1428C>T(p.Phe476=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,614,124 control chromosomes in the GnomAD database, including 8,961 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3760 hom., cov: 33)
  • Exomes 𝑓: 0.042 (5201 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.895

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-6445150-C-T is Benign according to our data. Variant chr8-6445150-C-T is described in ClinVar as [Benign]. Clinvar id is 96128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6445150-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.895 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.1428C>T	p.Phe476=	synonymous_variant	8/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.1428C>T	p.Phe476=	synonymous_variant	8/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21858 AN: 152124 Hom.: 3747 Cov.: 33

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.0795 AC: 19828 AN: 249454 Hom.: 2173 AF XY: 0.0761 AC XY: 10298 AN XY: 135350

Gnomad AFR exome AF: 0.430

Gnomad AMR exome AF: 0.0610

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0423 AC: 61889 AN: 1461882 Hom.: 5201 Cov.: 53 AF XY: 0.0440 AC XY: 32006 AN XY: 727246

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.0363

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0666

GnomAD4 genome AF: 0.144 AC: 21911 AN: 152242 Hom.: 3760 Cov.: 33 AF XY: 0.143 AC XY: 10633 AN XY: 74442

Gnomad4 AFR AF: 0.409

Gnomad4 AMR AF: 0.0812

Gnomad4 ASJ AF: 0.0377

Gnomad4 EAS AF: 0.161

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0392

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.130

Alfa AF: 0.0558 Hom.: 1467

Bravo AF: 0.158

Asia WGS AF: 0.166 AC: 578 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 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	- -

not provided Benign:2

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

Microcephaly 1, primary, autosomal recessive Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.63
Dann	Benign	0.40

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: rs2920676; hg19: chr8-6302671; COSMIC: COSV60920903;