8-6621435-A-G

Position:

• chr8-6621435-A-G

Variant summary

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

The NM_024596.5(MCPH1):​c.2215-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,605,044 control chromosomes in the GnomAD database, including 154,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15164 hom., cov: 32)
  • Exomes 𝑓: 0.43 (139347 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.602

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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-6621435-A-G is Benign according to our data. Variant chr8-6621435-A-G is described in ClinVar as [Benign]. Clinvar id is 158843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6621435-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2215-19A>G		intron_variant		ENST00000344683.10	NP_078872.3
MCPH1-AS1	NR_125386.1	n.430T>C		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2215-19A>G		intron_variant		1	NM_024596.5	ENSP00000342924	P1
MCPH1-AS1	ENST00000661193.1	n.1055-1211T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67318 AN: 151768 Hom.: 15136 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.437

GnomAD3 exomes AF: 0.447 AC: 110722 AN: 247942 Hom.: 25541 AF XY: 0.448 AC XY: 60272 AN XY: 134682

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.671

Gnomad SAS exome AF: 0.502

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.419

GnomAD4 exome AF: 0.433 AC: 629535 AN: 1453158 Hom.: 139347 Cov.: 40 AF XY: 0.435 AC XY: 314823 AN XY: 723320

Gnomad4 AFR exome AF: 0.477

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.341

Gnomad4 EAS exome AF: 0.685

Gnomad4 SAS exome AF: 0.509

Gnomad4 FIN exome AF: 0.450

Gnomad4 NFE exome AF: 0.420

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.444 AC: 67395 AN: 151886 Hom.: 15164 Cov.: 32 AF XY: 0.448 AC XY: 33219 AN XY: 74214

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.681

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.443

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.436

Alfa AF: 0.370 Hom.: 2509

Bravo AF: 0.441

Asia WGS AF: 0.541 AC: 1884 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Microcephaly 1, primary, autosomal recessive Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.38

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: rs2936531; hg19: chr8-6478956;