rs115088000

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024596.5(MCPH1):c.989A>G(p.Tyr330Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,614,078 control chromosomes in the GnomAD database, including 10 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 6 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002575636).

BP6

Variant 8-6444711-A-G is Benign according to our data. Variant chr8-6444711-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 287122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6444711-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00315 (480/152282) while in subpopulation AFR AF= 0.011 (456/41566). AF 95% confidence interval is 0.0101. There are 4 homozygotes in gnomad4. There are 236 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.989A>G	p.Tyr330Cys	missense_variant	Exon 8 of 14	ENST00000344683.10	NP_078872.3	Q8NEM0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 link	c.989A>G	p.Tyr330Cys	missense_variant	Exon 8 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.00315

AC:

479

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000823

AC:

205

AN:

249110

Hom.:

AF XY:

0.000636

AC XY:

AN XY:

135240

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.000812

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000348

AC:

508

AN:

1461796

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

214

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0115

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.00315

AC:

480

AN:

152282

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

236

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0110

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000560

Hom.:

Bravo

AF:

0.00343

ESP6500AA

AF:

0.0108

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000852

AC:

103

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 25, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

May 05, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly 1, primary, autosomal recessive

Benign:1

Oct 03, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

MCPH1-related disorder

Benign:1

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

0.079

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.047

DANN

Benign

0.59

DEOGEN2

Benign

0.090

T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.011

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.0050

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.075

MVP

0.21

ClinPred

0.0014

GERP RS

-7.2

Varity_R

0.28

gMVP

0.10

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

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