8-6621465-C-T

Position:

chr8-6621465-C-T

Variant summary

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

The NM_024596.5(MCPH1):c.2226C>T(p.Ser742=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,609,454 control chromosomes in the GnomAD database, including 139,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12661 hom., cov: 33)

Exomes 𝑓: 0.41 ( 126529 hom. )

Consequence

MCPH1
NM_024596.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.596

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=-0.82).

BP6

Variant 8-6621465-C-T is Benign according to our data. Variant chr8-6621465-C-T is described in ClinVar as [Benign]. Clinvar id is 158844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6621465-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.596 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 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.2226C>T	p.Ser742=	synonymous_variant	13/14	ENST00000344683.10	NP_078872.3
MCPH1-AS1	NR_125386.1 linkuse as main transcript	n.400G>A		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 linkuse as main transcript	c.2226C>T	p.Ser742=	synonymous_variant	13/14	1	NM_024596.5	ENSP00000342924	P1	Q8NEM0-1
MCPH1-AS1	ENST00000661193.1 linkuse as main transcript	n.1055-1241G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.403

AC:

61191

AN:

151902

Hom.:

12645

Cov.:

show subpopulations

Gnomad AFR

AF:

0.363

Gnomad AMI

AF:

0.326

Gnomad AMR

AF:

0.380

Gnomad ASJ

AF:

0.339

Gnomad EAS

AF:

0.675

Gnomad SAS

AF:

0.492

Gnomad FIN

AF:

0.438

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.404

Gnomad OTH

AF:

0.409

GnomAD3 exomes

AF:

0.428

AC:

106400

AN:

248850

Hom.:

23588

AF XY:

0.430

AC XY:

58060

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.366

Gnomad AMR exome

AF:

0.391

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.667

Gnomad SAS exome

AF:

0.487

Gnomad FIN exome

AF:

0.438

Gnomad NFE exome

AF:

0.401

Gnomad OTH exome

AF:

0.402

GnomAD4 exome

AF:

0.412

AC:

600865

AN:

1457434

Hom.:

126529

Cov.:

AF XY:

0.415

AC XY:

300822

AN XY:

725226

show subpopulations

Gnomad4 AFR exome

AF:

0.366

Gnomad4 AMR exome

AF:

0.389

Gnomad4 ASJ exome

AF:

0.331

Gnomad4 EAS exome

AF:

0.681

Gnomad4 SAS exome

AF:

0.493

Gnomad4 FIN exome

AF:

0.445

Gnomad4 NFE exome

AF:

0.399

Gnomad4 OTH exome

AF:

0.406

GnomAD4 genome

AF:

0.403

AC:

61245

AN:

152020

Hom.:

12661

Cov.:

AF XY:

0.408

AC XY:

30340

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.363

Gnomad4 AMR

AF:

0.380

Gnomad4 ASJ

AF:

0.339

Gnomad4 EAS

AF:

0.675

Gnomad4 SAS

AF:

0.492

Gnomad4 FIN

AF:

0.438

Gnomad4 NFE

AF:

0.404

Gnomad4 OTH

AF:

0.408

Alfa

AF:

0.397

Hom.:

14109

Bravo

AF:

0.397

Asia WGS

AF:

0.529

AC:

1843

AN:

3478

EpiCase

AF:

0.395

EpiControl

AF:

0.393

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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, 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

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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

-0.82

CADD

Benign

2.2

DANN

Benign

0.77

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

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