8-6414635-G-A

Position:

• chr8-6414635-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024596.5(MCPH1):​c.115-130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 906,062 control chromosomes in the GnomAD database, including 263,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.65 (35945 hom., cov: 33)
  • Exomes 𝑓: 0.77 (227583 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.458

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-6414635-G-A is Benign according to our data. Variant chr8-6414635-G-A is described in ClinVar as [Benign]. Clinvar id is 673332.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.115-130G>A		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.115-130G>A		intron_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98902 AN: 152054 Hom.: 35938 Cov.: 33

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.668

GnomAD4 exome AF: 0.772 AC: 581627 AN: 753890 Hom.: 227583 AF XY: 0.771 AC XY: 299476 AN XY: 388580

Gnomad4 AFR exome AF: 0.283

Gnomad4 AMR exome AF: 0.824

Gnomad4 ASJ exome AF: 0.678

Gnomad4 EAS exome AF: 0.762

Gnomad4 SAS exome AF: 0.731

Gnomad4 FIN exome AF: 0.876

Gnomad4 NFE exome AF: 0.790

Gnomad4 OTH exome AF: 0.738

GnomAD4 genome AF: 0.650 AC: 98924 AN: 152172 Hom.: 35945 Cov.: 33 AF XY: 0.658 AC XY: 48996 AN XY: 74420

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.769

Gnomad4 ASJ AF: 0.685

Gnomad4 EAS AF: 0.748

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.877

Gnomad4 NFE AF: 0.788

Gnomad4 OTH AF: 0.670

Alfa AF: 0.752 Hom.: 21938

Bravo AF: 0.628

Asia WGS AF: 0.712 AC: 2473 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.90
CADD	Benign	2.0
DANN	Benign	0.81

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: rs2442546; hg19: chr8-6272156;