rs34121009

chr8-6444512-A-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.790A>G(p.Ile264Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 1,614,112 control chromosomes in the GnomAD database, including 738 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (419 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (319 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.435

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=0.0014106929).
• BP6: Variant 8-6444512-A-G is Benign according to our data. Variant chr8-6444512-A-G is described in ClinVar as [Benign]. Clinvar id is 158875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6444512-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.790A>G	p.Ile264Val	missense_variant	8/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.790A>G	p.Ile264Val	missense_variant	8/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5885 AN: 152152 Hom.: 417 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0100 AC: 2506 AN: 249432 Hom.: 152 AF XY: 0.00737 AC XY: 998 AN XY: 135322

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.00852

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00397 AC: 5809 AN: 1461844 Hom.: 319 Cov.: 31 AF XY: 0.00341 AC XY: 2479 AN XY: 727226

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.00910

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.00940

GnomAD4 genome AF: 0.0387 AC: 5897 AN: 152268 Hom.: 419 Cov.: 33 AF XY: 0.0370 AC XY: 2758 AN XY: 74468

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.00818 Hom.: 109

Bravo AF: 0.0451

ESP6500AA AF: 0.128 AC: 480

ESP6500EA AF: 0.000730 AC: 6

ExAC AF: 0.0123 AC: 1492

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 11, 2013

- -

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. -

MCPH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.22
Dann	Benign	0.21
DEOGEN2	Benign	0.053	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0045	N
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.24	N;N;N
REVEL	Benign	0.022
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.0090
ClinPred		0.00016	T
GERP RS		-6.5
Varity_R		0.0084
gMVP		0.084

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: rs34121009; hg19: chr8-6302033;