chr8-6445888-T-G

Position:

• chr8-6445888-T-G

Variant summary

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

The NM_001172574.2(MCPH1):​c.*333T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,038,434 control chromosomes in the GnomAD database, including 21,939 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 (7019 hom., cov: 33)
  • Exomes 𝑓: 0.18 (14920 hom.)
• Consequence: MCPH1 NM_001172574.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.317

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1825+341T>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.1825+341T>G		intron_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40159 AN: 152012 Hom.: 7003 Cov.: 33

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.176 AC: 156223 AN: 886304 Hom.: 14920 Cov.: 25 AF XY: 0.176 AC XY: 72482 AN XY: 411974

Gnomad4 AFR exome AF: 0.518

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.0873

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.264 AC: 40212 AN: 152130 Hom.: 7019 Cov.: 33 AF XY: 0.257 AC XY: 19136 AN XY: 74404

Gnomad4 AFR AF: 0.499

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.264

Alfa AF: 0.182 Hom.: 2967

Bravo AF: 0.279

Asia WGS AF: 0.224 AC: 781 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2916750; hg19: chr8-6303409;