rs587783741

Variant names:

• chr8-6431543-C-A
• rs587783741
• NM_024596.5:c.278C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6431543-C-A
• chr8-6431543-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_024596.5(MCPH1):​c.278C>A​(p.Ala93Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A93T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.53
• 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 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• PP5: Variant 8-6431543-C-A is Pathogenic according to our data. Variant chr8-6431543-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 158867.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.278C>A	p.Ala93Glu	missense	Exon 4 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.278C>A	p.Ala93Glu	missense	Exon 4 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.278C>A	p.Ala93Glu	missense	Exon 4 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.278C>A	p.Ala93Glu	missense	Exon 4 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.278C>A	p.Ala93Glu	missense	Exon 4 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.278C>A	p.Ala93Glu	missense	Exon 4 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000497 Hom.: 0

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.5
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.47		Gain of solvent accessibility (P = 9e-04)
MVP		0.76
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.62
Mutation Taster		=30/70	disease causing (ClinVar)

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: rs587783741; hg19: chr8-6289064;