8-6621439-C-G

Position:

• chr8-6621439-C-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.2215-15C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,606,776 control chromosomes in the GnomAD database, including 64,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5265 hom., cov: 33)
  • Exomes 𝑓: 0.28 (59324 hom.)
• Consequence: MCPH1 NM_024596.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.593

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=-0.85).
• BP6: Variant 8-6621439-C-G is Benign according to our data. Variant chr8-6621439-C-G is described in ClinVar as [Benign]. Clinvar id is 158842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6621439-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2215-15C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000344683.10	NP_078872.3
MCPH1-AS1	NR_125386.1	n.426G>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.2215-15C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_024596.5	ENSP00000342924	P1
MCPH1-AS1	ENST00000661193.1	n.1055-1215G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39445 AN: 151950 Hom.: 5258 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.243 AC: 60373 AN: 248108 Hom.: 8007 AF XY: 0.250 AC XY: 33622 AN XY: 134750

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.0625

Gnomad SAS exome AF: 0.274

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.281 AC: 408159 AN: 1454708 Hom.: 59324 Cov.: 42 AF XY: 0.281 AC XY: 203163 AN XY: 723968

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.260 AC: 39482 AN: 152068 Hom.: 5265 Cov.: 33 AF XY: 0.256 AC XY: 19004 AN XY: 74304

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.230

Gnomad4 EAS AF: 0.0742

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.258

Alfa AF: 0.194 Hom.: 583

Bravo AF: 0.253

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

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

Microcephaly 1, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11137040; hg19: chr8-6478960;