rs2440432

Positions:

• chr8-6487253-T-G

Variant summary

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

The NM_024596.5(MCPH1):​c.2136+6377T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 152,170 control chromosomes in the GnomAD database, including 6,477 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 0.29 (6477 hom., cov: 33)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.733

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2136+6377T>G		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2136+6377T>G		intron_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43474 AN: 152052 Hom.: 6470 Cov.: 33

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.286

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

GnomAD4 genome AF: 0.286 AC: 43504 AN: 152170 Hom.: 6477 Cov.: 33 AF XY: 0.281 AC XY: 20925 AN XY: 74390

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.284

Alfa AF: 0.284 Hom.: 766

Bravo AF: 0.287

Asia WGS AF: 0.230 AC: 801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.41
DANN	Benign	0.49

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: rs2440432; hg19: chr8-6344774;