NM_024596.5:c.2237T>A

Variant names:

• chr8-6621476-T-A
• NM_024596.5:c.2237T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024596.5(MCPH1):​c.2237T>A​(p.Leu746*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCPH1 NM_024596.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.90
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-6621476-T-A is Pathogenic according to our data. Variant chr8-6621476-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3595816.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2237T>A	p.Leu746*	stop_gained	Exon 13 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2237T>A	p.Leu746*	stop_gained	Exon 13 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.2237T>A	p.Leu746*	stop_gained	Exon 13 of 14	NP_001397846.1	A0A8I5KPV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2237T>A	p.Leu746*	stop_gained	Exon 13 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000692836.1		c.2237T>A	p.Leu746*	stop_gained	Exon 13 of 13	ENSP00000509971.1	A0A8I5KX36
	MCPH1	ENST00000689348.1		c.2237T>A	p.Leu746*	stop_gained	Exon 13 of 15	ENSP00000509554.1	A0A8I5KV10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Microcephaly 1, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	38
DANN	Benign	0.97
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.099	N
PhyloP100		1.9
Vest4		0.72
GERP RS		1.4
Mutation Taster		=7/193	disease causing (fs/PTC)

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

Other links and lift over

hg19: chr8-6478997;