Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate
The NM_024596.5(MCPH1):c.22+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).
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]
Our verdict: Likely_benign. The variant received -4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
Variant 8-6406697-A-G is Benign according to our data. Variant chr8-6406697-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2833473.Status of the report is criteria_provided_single_submitter, 1 stars.
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33456
American (AMR)
AF:
0.00
AC:
0
AN:
44640
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26050
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39640
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86014
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52430
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5748
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111396
Other (OTH)
AF:
0.00
AC:
0
AN:
60272
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.