rs2912016

chr8-6621657-C-Achr8-6621657-C-G

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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. A806A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.37 (10740 hom., cov: 33)
  • Exomes 𝑓: 0.36 (95947 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.28

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 -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	UniProt
MCPH1	NM_024596.5	c.2418C>A	p.Ala806=	synonymous_variant	13/14	ENST00000344683.10
MCPH1-AS1	NR_125386.1	n.230-22G>T		intron_variant, non_coding_transcript_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56918 AN: 151976 Hom.: 10722 Cov.: 33

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

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.: 43 AF XY: 0.363 AC XY: 263955 AN XY: 727124

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.: 33 AF XY: 0.377 AC XY: 28055 AN XY: 74328

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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	Eurofins Ntd Llc (ga)	Apr 10, 2014	- -
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	Genome-Nilou Lab	Sep 05, 2021	- -
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	- -

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	- -

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

Other links and lift over

dbSNP: rs2912016; hg19: chr8-6479178; COSMIC: COSV60911550; COSMIC: COSV60911550;