chr8-6406672-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_024596.5(MCPH1):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0620
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-DT (HGNC:55599): (MCPH1 divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a domain BRCT 1 (size 92) in uniprot entity MCPH1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_024596.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16162893).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MCPH1NM_024596.5 linkuse as main transcriptc.5C>T p.Ala2Val missense_variant 1/14 ENST00000344683.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MCPH1ENST00000344683.10 linkuse as main transcriptc.5C>T p.Ala2Val missense_variant 1/141 NM_024596.5 P1Q8NEM0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000417
AC:
1
AN:
240022
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
131838
show subpopulations
Gnomad AFR exome
AF:
0.0000698
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1459606
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726076
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000680
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000166
AC:
2

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 submitterclinical testingInvitaeOct 10, 2021This sequence change replaces alanine with valine at codon 2 of the MCPH1 protein (p.Ala2Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs759488210, ExAC 0.01%). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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
Uncertain
0.37
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
T;.;.
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.045
N
M_CAP
Benign
0.0062
T
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.69
N;N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.61
N;N;N
REVEL
Benign
0.047
Sift
Uncertain
0.0080
D;D;D
Sift4G
Benign
0.12
T;T;T
Polyphen
0.95
P;.;.
Vest4
0.22
MutPred
0.39
Loss of disorder (P = 0.059);Loss of disorder (P = 0.059);Loss of disorder (P = 0.059);
MVP
0.43
ClinPred
0.38
T
GERP RS
1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.13
gMVP
0.32

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.

Other links and lift over

dbSNP: rs759488210; hg19: chr8-6264193; API