8-6444633-G-T

Variant summary

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

The NM_024596.5(MCPH1):​c.911G>T​(p.Arg304Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,613,798 control chromosomes in the GnomAD database, including 16,233 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1092 hom., cov: 33)
Exomes 𝑓: 0.14 ( 15141 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

3
14

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.646
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]

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=8.748174E-4).
BP6
Variant 8-6444633-G-T is Benign according to our data. Variant chr8-6444633-G-T is described in ClinVar as [Benign]. Clinvar id is 158879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6444633-G-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MCPH1NM_024596.5 linkuse as main transcriptc.911G>T p.Arg304Ile missense_variant 8/14 ENST00000344683.10 NP_078872.3 Q8NEM0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MCPH1ENST00000344683.10 linkuse as main transcriptc.911G>T p.Arg304Ile missense_variant 8/141 NM_024596.5 ENSP00000342924.5 Q8NEM0-1

Frequencies

GnomAD3 genomes
AF:
0.107
AC:
16249
AN:
152092
Hom.:
1092
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0425
Gnomad AMI
AF:
0.102
Gnomad AMR
AF:
0.0999
Gnomad ASJ
AF:
0.258
Gnomad EAS
AF:
0.0210
Gnomad SAS
AF:
0.0873
Gnomad FIN
AF:
0.0679
Gnomad MID
AF:
0.228
Gnomad NFE
AF:
0.153
Gnomad OTH
AF:
0.128
GnomAD3 exomes
AF:
0.113
AC:
28259
AN:
249024
Hom.:
2080
AF XY:
0.116
AC XY:
15740
AN XY:
135174
show subpopulations
Gnomad AFR exome
AF:
0.0355
Gnomad AMR exome
AF:
0.0673
Gnomad ASJ exome
AF:
0.269
Gnomad EAS exome
AF:
0.0174
Gnomad SAS exome
AF:
0.0863
Gnomad FIN exome
AF:
0.0646
Gnomad NFE exome
AF:
0.155
Gnomad OTH exome
AF:
0.139
GnomAD4 exome
AF:
0.139
AC:
202430
AN:
1461584
Hom.:
15141
Cov.:
34
AF XY:
0.138
AC XY:
100356
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.0379
Gnomad4 AMR exome
AF:
0.0725
Gnomad4 ASJ exome
AF:
0.271
Gnomad4 EAS exome
AF:
0.0331
Gnomad4 SAS exome
AF:
0.0871
Gnomad4 FIN exome
AF:
0.0692
Gnomad4 NFE exome
AF:
0.152
Gnomad4 OTH exome
AF:
0.139
GnomAD4 genome
AF:
0.107
AC:
16245
AN:
152214
Hom.:
1092
Cov.:
33
AF XY:
0.101
AC XY:
7528
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.0423
Gnomad4 AMR
AF:
0.0997
Gnomad4 ASJ
AF:
0.258
Gnomad4 EAS
AF:
0.0208
Gnomad4 SAS
AF:
0.0871
Gnomad4 FIN
AF:
0.0679
Gnomad4 NFE
AF:
0.153
Gnomad4 OTH
AF:
0.126
Alfa
AF:
0.150
Hom.:
3929
Bravo
AF:
0.106
TwinsUK
AF:
0.159
AC:
588
ALSPAC
AF:
0.153
AC:
589
ESP6500AA
AF:
0.0397
AC:
147
ESP6500EA
AF:
0.154
AC:
1256
ExAC
AF:
0.115
AC:
13897
Asia WGS
AF:
0.0560
AC:
195
AN:
3478
EpiCase
AF:
0.167
EpiControl
AF:
0.166

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsAug 02, 2017- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Microcephaly 1, primary, autosomal recessive Benign:3
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterJun 28, 2017- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.69
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
14
DANN
Benign
0.97
DEOGEN2
Benign
0.18
T;.;.
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.075
N
MetaRNN
Benign
0.00087
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.0
M;M;.
PrimateAI
Benign
0.23
T
PROVEAN
Uncertain
-2.9
D;D;D
REVEL
Benign
0.049
Sift
Uncertain
0.0080
D;D;D
Sift4G
Benign
0.090
T;T;T
Polyphen
0.99
D;.;.
Vest4
0.077
ClinPred
0.030
T
GERP RS
-2.2
Varity_R
0.14
gMVP
0.17

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.

Other links and lift over

dbSNP: rs2083914; hg19: chr8-6302154; COSMIC: COSV60917544; API