rs2290145

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024596.5(MCPH1):c.305G>A(p.Ser102Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,609,524 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S102T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034677148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5 linkuse as main transcript	c.305G>A	p.Ser102Asn	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>A	p.Ser102Asn	missense_variant	4/14	1	NM_024596.5	P1	Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000283

AC:

AN:

247560

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000391

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1457740

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000657

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151784

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74100

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2021

This sequence change replaces serine with asparagine at codon 102 of the MCPH1 protein (p.Ser102Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs2290145, ExAC 0.06%). This variant has not been reported in the literature in individuals affected with MCPH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.13

T;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.023

M_CAP

Benign

0.0092

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

M;M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.67

N;N;N

REVEL

Benign

0.033

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.84

P;.;.

Vest4

0.095

MutPred

0.19

Gain of MoRF binding (P = 0.12);Gain of MoRF binding (P = 0.12);Gain of MoRF binding (P = 0.12);

MVP

0.32

ClinPred

0.027

GERP RS

-0.079

Varity_R

0.032

gMVP

0.21

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