rs12674488

chr8-6480785-C-Achr8-6480785-C-G

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.2045C>A(p.Thr682Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,986 control chromosomes in the GnomAD database, including 19,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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. T682T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1574 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17785 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.11

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=9.829998E-4).
• BP6: Variant 8-6480785-C-A is Benign according to our data. Variant chr8-6480785-C-A is described in ClinVar as [Benign]. Clinvar id is 158834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6480785-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.2045C>A	p.Thr682Asn	missense_variant	11/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.2045C>A	p.Thr682Asn	missense_variant	11/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20642 AN: 152058 Hom.: 1575 Cov.: 32

Gnomad AFR AF: 0.0945

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.149 AC: 37271 AN: 249570 Hom.: 3080 AF XY: 0.153 AC XY: 20761 AN XY: 135402

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.0853

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.153 AC: 223987 AN: 1461810 Hom.: 17785 Cov.: 33 AF XY: 0.155 AC XY: 112624 AN XY: 727222

Gnomad4 AFR exome AF: 0.0930

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.255

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.0888

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome AF: 0.136 AC: 20645 AN: 152176 Hom.: 1574 Cov.: 32 AF XY: 0.133 AC XY: 9893 AN XY: 74394

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.0925

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.161

Alfa AF: 0.154 Hom.: 3686

Bravo AF: 0.134

TwinsUK AF: 0.154 AC: 570

ALSPAC AF: 0.158 AC: 609

ESP6500AA AF: 0.0843 AC: 335

ESP6500EA AF: 0.156 AC: 1301

ExAC AF: 0.152 AC: 18389

Asia WGS AF: 0.163 AC: 569 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.175

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	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	Athena Diagnostics	Aug 02, 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	- -

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.52	D
MetaRNN	Benign	0.00098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.094	T
Sift4G	Uncertain	0.020	D
Polyphen		0.98	D
Vest4		0.086
ClinPred		0.021	T
GERP RS		0.67
Varity_R		0.16
gMVP		0.23

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: rs12674488; hg19: chr8-6338306;