8-6442011-A-G

Position:

• chr8-6442011-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000344683.10(MCPH1):​c.581-56A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,238,778 control chromosomes in the GnomAD database, including 404,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (40753 hom., cov: 32)
  • Exomes 𝑓: 0.81 (363533 hom.)
• Consequence: MCPH1 ENST00000344683.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0930

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-6442011-A-G is Benign according to our data. Variant chr8-6442011-A-G is described in ClinVar as [Benign]. Clinvar id is 673931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.581-56A>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.581-56A>G		intron_variant		1	NM_024596.5	ENSP00000342924	P1

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107359 AN: 152020 Hom.: 40742 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.712

GnomAD4 exome AF: 0.814 AC: 884770 AN: 1086640 Hom.: 363533 Cov.: 14 AF XY: 0.814 AC XY: 454157 AN XY: 558192

Gnomad4 AFR exome AF: 0.386

Gnomad4 AMR exome AF: 0.860

Gnomad4 ASJ exome AF: 0.688

Gnomad4 EAS exome AF: 0.813

Gnomad4 SAS exome AF: 0.763

Gnomad4 FIN exome AF: 0.896

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 0.783

GnomAD4 genome AF: 0.706 AC: 107398 AN: 152138 Hom.: 40753 Cov.: 32 AF XY: 0.713 AC XY: 53060 AN XY: 74382

Gnomad4 AFR AF: 0.398

Gnomad4 AMR AF: 0.803

Gnomad4 ASJ AF: 0.698

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.754

Gnomad4 FIN AF: 0.893

Gnomad4 NFE AF: 0.829

Gnomad4 OTH AF: 0.714

Alfa AF: 0.765 Hom.: 6502

Bravo AF: 0.688

Asia WGS AF: 0.769 AC: 2671 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.58
DANN	Benign	0.76

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: rs2053618; hg19: chr8-6299532;