8-6621521-C-A

Variant names:

• chr8-6621521-C-A
• rs1057090
• NM_024596.5:c.2282C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_024596.5(MCPH1):​c.2282C>A​(p.Ala761Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A761V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.503
• Publications: 46 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11304143).
• BP6: Variant 8-6621521-C-A is Benign according to our data. Variant chr8-6621521-C-A is described in ClinVar as Benign. ClinVar VariationId is 158848.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2282C>A	p.Ala761Glu	missense	Exon 13 of 14	NP_078872.3
	MCPH1	NM_001322042.2		c.2282C>A	p.Ala761Glu	missense	Exon 13 of 15	NP_001308971.2
	MCPH1	NM_001410917.1		c.2282C>A	p.Ala761Glu	missense	Exon 13 of 14	NP_001397846.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2282C>A	p.Ala761Glu	missense	Exon 13 of 14	ENSP00000342924.5
	MCPH1	ENST00000692836.1		c.2282C>A	p.Ala761Glu	missense	Exon 13 of 13	ENSP00000509971.1
	MCPH1	ENST00000689348.1		c.2282C>A	p.Ala761Glu	missense	Exon 13 of 15	ENSP00000509554.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.5
DANN	Benign	0.91
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.025	N
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.15	T
PhyloP100		-0.50
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.28
Sift	Benign	0.20	T
Sift4G	Benign	0.15	T
Vest4		0.18
MutPred		0.47		Gain of disorder (P = 0.0541)
MVP		0.27
ClinPred		0.095	T
GERP RS		-8.3
Varity_R		0.079
gMVP		0.66
Mutation Taster		=97/3	polymorphism

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

dbSNP: rs1057090; hg19: chr8-6479042;