8-6431570-G-C

Position:

chr8-6431570-G-C

Variant summary

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

The NM_024596.5(MCPH1):c.305G>C(p.Ser102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,609,642 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S102N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.282

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=0.004864216).

BP6

Variant 8-6431570-G-C is Benign according to our data. Variant chr8-6431570-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 158868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6431570-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00221 (335/151900) while in subpopulation AFR AF= 0.00782 (324/41414). AF 95% confidence interval is 0.00712. There are 4 homozygotes in gnomad4. There are 174 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/exons	MANE	UniProt
MCPH1	NM_024596.5 linkuse as main transcript	c.305G>C	p.Ser102Thr	missense_variant	4/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10 linkuse as main transcript	c.305G>C	p.Ser102Thr	missense_variant	4/14	1	NM_024596.5	P1	Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

335

AN:

151782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00785

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000537

AC:

133

AN:

247560

Hom.:

AF XY:

0.000410

AC XY:

AN XY:

134300

show subpopulations

Gnomad AFR exome

AF:

0.00825

Gnomad AMR exome

AF:

0.000117

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000215

AC:

313

AN:

1457742

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

125

AN XY:

725164

show subpopulations

Gnomad4 AFR exome

AF:

0.00815

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000481

GnomAD4 genome

AF:

0.00221

AC:

335

AN:

151900

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00782

Gnomad4 AMR

AF:

0.000525

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.00254

ESP6500AA

AF:

0.00743

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000588

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2018	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. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 09, 2018	- -

MCPH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

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

0.081

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.32

T;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.065

M_CAP

Benign

0.0049

MetaRNN

Benign

0.0049

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.022

Sift

Benign

0.10

T;T;D

Sift4G

Benign

0.67

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.14

MVP

0.43

ClinPred

0.0087

GERP RS

-0.079

Varity_R

0.054

gMVP

0.22

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