8-6487607-G-C

Position:

• chr8-6487607-G-C

Variant summary

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

The NM_024596.5(MCPH1):​c.2136+6731G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,078 control chromosomes in the GnomAD database, including 5,228 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 0.26 (5228 hom., cov: 33)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.119

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.2136+6731G>C		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.2136+6731G>C		intron_variant		1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39343 AN: 151960 Hom.: 5224 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.268

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

GnomAD4 genome AF: 0.259 AC: 39356 AN: 152078 Hom.: 5228 Cov.: 33 AF XY: 0.255 AC XY: 18931 AN XY: 74328

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.267

Alfa AF: 0.156 Hom.: 278

Bravo AF: 0.256

Asia WGS AF: 0.223 AC: 779 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.86
DANN	Benign	0.46

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: rs2442485; hg19: chr8-6345128;