rs2442517

chr8-6434003-A-Gchr8-6434003-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):c.322-2045A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 151,868 control chromosomes in the GnomAD database, including 15,306 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (15306 hom., cov: 31)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.475

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.322-2045A>G		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.322-2045A>G		intron_variant		1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65126 AN: 151748 Hom.: 15304 Cov.: 31

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.463

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.429 AC: 65140 AN: 151868 Hom.: 15306 Cov.: 31 AF XY: 0.441 AC XY: 32733 AN XY: 74212

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.529

Gnomad4 ASJ AF: 0.475

Gnomad4 EAS AF: 0.758

Gnomad4 SAS AF: 0.621

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.468

Gnomad4 OTH AF: 0.468

Alfa AF: 0.469 Hom.: 33986

Bravo AF: 0.420

Asia WGS AF: 0.668 AC: 2319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.52
Dann	Benign	0.35

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: rs2442517; hg19: chr8-6291524;