chr8-6408449-TAGCCTCAAGCAATCCTCCCGCCTCCACCTTGCAAAATGCTGGGATTACAGGCATGAGCTACTTTGTTCAGCCAGTAGAAGAAACTTCATTTACTTTTCTTATTTTTGAGGCAAGGTCTTTCTCTGCTGCCCAGGCTGGAGTGCAATGGTGCGATCATAACTCAGCTTCTACCTCCTGGGCTCTAGGGATTCTCCCACCTCAGCTTCTCCACCCTACCCACCCCCATTTCCCACCCAGTAGCTGGGACTACAGCCACTCGCCACCATTCCTGGCTAATTAAAAACAAAATTTTTTTTAGAGACAGGGTTTCACTATGTTGCCCAGGCTGGTCTCAAACTTCTGTGCCCAAGTGATCCCACTGCCTTGGCCTTCCAGAGTGCTGCAATTACAGCATGAGCCACCACACCTGGCCAGTAGAGTAAATTTTTGTTTTACTTTTTTCTTTTTTTTTTTTTGAAACGGGTCTCGCCCTGTCACCCAGGCTGGAGTGCAATGGCGCAATCTCGGCTCACTGCAACCTCTGCCTCCCGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCAGTAGCTGGGATTACAGGTGCCCGCCACCATGCTCGGCTAATTTTTTGTATCTTTTAGTAGAGATGGTTTTTCACCATGTTGGCCCGGCTGGTCTCAAACCCCTGACTTCGTGGATCCACCCACTTCCGCCTCCCACAGTGCTGGGATTACAGGCGTGAGCCACTGTGCCGGCCTCGGTTTACTCTTAAATGTAAATAGAACAAAATCTATTGGGCAGGGGATGCTGGAATTTCAAATGTATGTTTCATGTTCATATCTTGTTTTCAGATGTAG-T

Position:

• chr8-6408449-TAGCCTCAAGCAATCCTCCCGCCTCCACCTTGCAAAATGCTGGGATTACAGGCATGAGCTACTTTGTTCAGCCAGTAGAAGAAACTTCATTTACTTTTCTTATTTTTGAGGCAAGGTCTTTCTCTGCTGCCCAGGCTGGAGTGCAATGGTGCGATCATAACTCAGCTTCTACCTCCTGGGCTCTAGGGATTCTCCCACCTCAGCTTCTCCACCCTACCCACCCCCATTTCCCACCCAGTAGCTGGGACTACAGCCACTCGCCACCATTCCTGGCTAATTAAAAACAAAATTTTTTTTAGAGACAGGGTTTCACTATGTTGCCCAGGCTGGTCTCAAACTTCTGTGCCCAAGTGATCCCACTGCCTTGGCCTTCCAGAGTGCTGCAATTACAGCATGAGCCACCACACCTGGCCAGTAGAGTAAATTTTTGTTTTACTTTTTTCTTTTTTTTTTTTTGAAACGGGTCTCGCCCTGTCACCCAGGCTGGAGTGCAATGGCGCAATCTCGGCTCACTGCAACCTCTGCCTCCCGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCAGTAGCTGGGATTACAGGTGCCCGCCACCATGCTCGGCTAATTTTTTGTATCTTTTAGTAGAGATGGTTTTTCACCATGTTGGCCCGGCTGGTCTCAAACCCCTGACTTCGTGGATCCACCCACTTCCGCCTCCCACAGTGCTGGGATTACAGGCGTGAGCCACTGTGCCGGCCTCGGTTTACTCTTAAATGTAAATAGAACAAAATCTATTGGGCAGGGGATGCTGGAATTTCAAATGTATGTTTCATGTTCATATCTTGTTTTCAGATGTAG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024596.5(MCPH1):​c.23-829_28del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCPH1 NM_024596.5 splice_acceptor, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.365

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-6408449-TAGCCTCAAGCAATCCTCCCGCCTCCACCTTGCAAAATGCTGGGATTACAGGCATGAGCTACTTTGTTCAGCCAGTAGAAGAAACTTCATTTACTTTTCTTATTTTTGAGGCAAGGTCTTTCTCTGCTGCCCAGGCTGGAGTGCAATGGTGCGATCATAACTCAGCTTCTACCTCCTGGGCTCTAGGGATTCTCCCACCTCAGCTTCTCCACCCTACCCACCCCCATTTCCCACCCAGTAGCTGGGACTACAGCCACTCGCCACCATTCCTGGCTAATTAAAAACAAAATTTTTTTTAGAGACAGGGTTTCACTATGTTGCCCAGGCTGGTCTCAAACTTCTGTGCCCAAGTGATCCCACTGCCTTGGCCTTCCAGAGTGCTGCAATTACAGCATGAGCCACCACACCTGGCCAGTAGAGTAAATTTTTGTTTTACTTTTTTCTTTTTTTTTTTTTGAAACGGGTCTCGCCCTGTCACCCAGGCTGGAGTGCAATGGCGCAATCTCGGCTCACTGCAACCTCTGCCTCCCGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCAGTAGCTGGGATTACAGGTGCCCGCCACCATGCTCGGCTAATTTTTTGTATCTTTTAGTAGAGATGGTTTTTCACCATGTTGGCCCGGCTGGTCTCAAACCCCTGACTTCGTGGATCCACCCACTTCCGCCTCCCACAGTGCTGGGATTACAGGCGTGAGCCACTGTGCCGGCCTCGGTTTACTCTTAAATGTAAATAGAACAAAATCTATTGGGCAGGGGATGCTGGAATTTCAAATGTATGTTTCATGTTCATATCTTGTTTTCAGATGTAG-T is Pathogenic according to our data. Variant chr8-6408449-TAGCCTCAAGCAATCCTCCCGCCTCCACCTTGCAAAATGCTGGGATTACAGGCATGAGCTACTTTGTTCAGCCAGTAGAAGAAACTTCATTTACTTTTCTTATTTTTGAGGCAAGGTCTTTCTCTGCTGCCCAGGCTGGAGTGCAATGGTGCGATCATAACTCAGCTTCTACCTCCTGGGCTCTAGGGATTCTCCCACCTCAGCTTCTCCACCCTACCCACCCCCATTTCCCACCCAGTAGCTGGGACTACAGCCACTCGCCACCATTCCTGGCTAATTAAAAACAAAATTTTTTTTAGAGACAGGGTTTCACTATGTTGCCCAGGCTGGTCTCAAACTTCTGTGCCCAAGTGATCCCACTGCCTTGGCCTTCCAGAGTGCTGCAATTACAGCATGAGCCACCACACCTGGCCAGTAGAGTAAATTTTTGTTTTACTTTTTTCTTTTTTTTTTTTTGAAACGGGTCTCGCCCTGTCACCCAGGCTGGAGTGCAATGGCGCAATCTCGGCTCACTGCAACCTCTGCCTCCCGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCAGTAGCTGGGATTACAGGTGCCCGCCACCATGCTCGGCTAATTTTTTGTATCTTTTAGTAGAGATGGTTTTTCACCATGTTGGCCCGGCTGGTCTCAAACCCCTGACTTCGTGGATCCACCCACTTCCGCCTCCCACAGTGCTGGGATTACAGGCGTGAGCCACTGTGCCGGCCTCGGTTTACTCTTAAATGTAAATAGAACAAAATCTATTGGGCAGGGGATGCTGGAATTTCAAATGTATGTTTCATGTTCATATCTTGTTTTCAGATGTAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2829540.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.23-829_28del		splice_acceptor_variant, coding_sequence_variant, intron_variant	2/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.23-829_28del		splice_acceptor_variant, coding_sequence_variant, intron_variant	2/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals affected with MCPH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 2 (c.23-829_28del) of the MCPH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MCPH1 are known to be pathogenic (PMID: 20978018). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-6265970;