8-6439029-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024596.5(MCPH1):c.513G>T(p.Arg171Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.973 in 1,612,852 control chromosomes in the GnomAD database, including 765,580 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.93 ( 65878 hom., cov: 31)

Exomes 𝑓: 0.98 ( 699702 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.351

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=8.9428073E-7).

BP6

Variant 8-6439029-G-T is Benign according to our data. Variant chr8-6439029-G-T is described in ClinVar as [Benign]. Clinvar id is 1174812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6439029-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.513G>T	p.Arg171Ser	missense_variant	Exon 6 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.513G>T	p.Arg171Ser	missense_variant	Exon 6 of 14	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.927

AC:

140850

AN:

152020

Hom.:

65849

Cov.:

show subpopulations

Gnomad AFR

AF:

0.782

Gnomad AMI

AF:

0.957

Gnomad AMR

AF:

0.966

Gnomad ASJ

AF:

0.977

Gnomad EAS

AF:

0.988

Gnomad SAS

AF:

0.954

Gnomad FIN

AF:

0.987

Gnomad MID

AF:

0.953

Gnomad NFE

AF:

0.985

Gnomad OTH

AF:

0.947

GnomAD3 exomes

AF:

0.969

AC:

241414

AN:

249192

Hom.:

117292

AF XY:

0.970

AC XY:

131250

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.771

Gnomad AMR exome

AF:

0.984

Gnomad ASJ exome

AF:

0.980

Gnomad EAS exome

AF:

0.989

Gnomad SAS exome

AF:

0.955

Gnomad FIN exome

AF:

0.989

Gnomad NFE exome

AF:

0.987

Gnomad OTH exome

AF:

0.978

GnomAD4 exome

AF:

0.978

AC:

1428796

AN:

1460714

Hom.:

699702

Cov.:

AF XY:

0.978

AC XY:

710733

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.766

Gnomad4 AMR exome

AF:

0.982

Gnomad4 ASJ exome

AF:

0.981

Gnomad4 EAS exome

AF:

0.993

Gnomad4 SAS exome

AF:

0.955

Gnomad4 FIN exome

AF:

0.989

Gnomad4 NFE exome

AF:

0.986

Gnomad4 OTH exome

AF:

0.967

GnomAD4 genome

AF:

0.926

AC:

140932

AN:

152138

Hom.:

65878

Cov.:

AF XY:

0.928

AC XY:

69018

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.782

Gnomad4 AMR

AF:

0.966

Gnomad4 ASJ

AF:

0.977

Gnomad4 EAS

AF:

0.988

Gnomad4 SAS

AF:

0.954

Gnomad4 FIN

AF:

0.987

Gnomad4 NFE

AF:

0.985

Gnomad4 OTH

AF:

0.947

Alfa

AF:

0.973

Hom.:

125948

Bravo

AF:

0.918

TwinsUK

AF:

0.985

AC:

3651

ALSPAC

AF:

0.981

AC:

3782

ESP6500AA

AF:

0.797

AC:

2997

ESP6500EA

AF:

0.983

AC:

8080

ExAC

AF:

0.966

AC:

116695

Asia WGS

AF:

0.953

AC:

3314

AN:

3478

EpiCase

AF:

0.984

EpiControl

AF:

0.986

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly 1, primary, autosomal recessive

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.32

DANN

Benign

0.44

DEOGEN2

Benign

0.079

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0020

MetaRNN

Benign

8.9e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

1.0

N;N

REVEL

Benign

0.013

Sift

Benign

0.86

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0

B;.

Vest4

0.043

MutPred

0.28

Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);

ClinPred

0.0013

GERP RS

-4.6

Varity_R

0.11

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