8-6621640-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024596.5(MCPH1):​c.2401A>T​(p.Ser801Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S801G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

1
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.550
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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07705626).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MCPH1NM_024596.5 linkuse as main transcriptc.2401A>T p.Ser801Cys missense_variant 13/14 ENST00000344683.10 NP_078872.3
MCPH1-AS1NR_125386.1 linkuse as main transcriptn.230-5T>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MCPH1ENST00000344683.10 linkuse as main transcriptc.2401A>T p.Ser801Cys missense_variant 13/141 NM_024596.5 ENSP00000342924 P1Q8NEM0-1
MCPH1-AS1ENST00000661193.1 linkuse as main transcriptn.1055-1416T>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461892
Hom.:
0
Cov.:
51
AF XY:
0.0000110
AC XY:
8
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
6.8
DANN
Benign
0.96
DEOGEN2
Benign
0.11
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.030
N
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.077
T
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
1.4
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.19
Sift
Benign
0.070
T
Sift4G
Uncertain
0.041
D
Polyphen
0.0010
B
Vest4
0.14
MutPred
0.41
Loss of disorder (P = 0.0024);
MVP
0.70
ClinPred
0.066
T
GERP RS
0.51
Varity_R
0.25
gMVP
0.26

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: rs45540031; hg19: chr8-6479161; API