NM_024596.5:c.7G>T

Variant names:

• chr8-6406674-G-T
• rs2129550282
• NM_024596.5:c.7G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024596.5(MCPH1):​c.7G>T​(p.Ala3Ser) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.520
• 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-DT (HGNC:55599): (MCPH1 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08617422).

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.7G>T	p.Ala3Ser	missense	Exon 1 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.7G>T	p.Ala3Ser	missense	Exon 1 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.7G>T	p.Ala3Ser	missense	Exon 1 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.7G>T	p.Ala3Ser	missense	Exon 1 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.7G>T	p.Ala3Ser	missense	Exon 1 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.7G>T	p.Ala3Ser	missense	Exon 1 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.45	N
PhyloP100		0.52
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.082
Sift	Uncertain	0.025	D
Sift4G	Benign	0.80	T
Polyphen		0.010	B
Vest4		0.15
MutPred		0.26		Gain of disorder (P = 0.0412)
MVP		0.27
ClinPred		0.60	D
GERP RS		1.2
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.29
Mutation Taster		=95/5	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: rs2129550282; hg19: chr8-6264195;