8-6444911-G-C

Position:

• chr8-6444911-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024596.5(MCPH1):​c.1189G>C​(p.Val397Leu) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045243323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1189G>C	p.Val397Leu	missense_variant	8/14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.1189G>C	p.Val397Leu	missense_variant	8/14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0010
DANN	Benign	0.49
DEOGEN2	Benign	0.056	T;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0087	N
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.027
MutPred		0.089		Loss of MoRF binding (P = 0.187);Loss of MoRF binding (P = 0.187);.;
MVP		0.10
ClinPred		0.057	T
GERP RS		-12
Varity_R		0.017
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs539491399; hg19: chr8-6302432; COSMIC: COSV60911975;