rs2922828

chr8-6442120-G-Achr8-6442120-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024596.5(MCPH1):c.634G>A(p.Ala212Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,298 control chromosomes in the GnomAD database, including 101 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (56 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (45 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0180

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=0.0016688406).
• BP6: Variant 8-6442120-G-A is Benign according to our data. Variant chr8-6442120-G-A is described in ClinVar as [Benign]. Clinvar id is 158872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6442120-G-A is described in Lovd as [Benign]. Variant chr8-6442120-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2257/152246) while in subpopulation AFR AF= 0.0509 (2115/41530). AF 95% confidence interval is 0.0491. There are 56 homozygotes in gnomad4. There are 1074 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.634G>A	p.Ala212Thr	missense_variant	7/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.634G>A	p.Ala212Thr	missense_variant	7/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2240 AN: 152128 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00363 AC: 905 AN: 249386 Hom.: 17 AF XY: 0.00281 AC XY: 380 AN XY: 135324

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00157 AC: 2288 AN: 1461052 Hom.: 45 Cov.: 30 AF XY: 0.00136 AC XY: 989 AN XY: 726900

Gnomad4 AFR exome AF: 0.0503

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.00409

GnomAD4 genome AF: 0.0148 AC: 2257 AN: 152246 Hom.: 56 Cov.: 33 AF XY: 0.0144 AC XY: 1074 AN XY: 74434

Gnomad4 AFR AF: 0.0509

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00211 Hom.: 14

Bravo AF: 0.0161

ESP6500AA AF: 0.0467 AC: 172

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00470 AC: 568

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Microcephaly 1, primary, autosomal recessive Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	7.8
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.039	N
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.93	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.31	B;.;.
Vest4		0.023
MVP		0.30
ClinPred		0.013	T
GERP RS		1.6
Varity_R		0.024
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2922828; hg19: chr8-6299641;