rs1550697

chr8-6409253-G-A

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.23-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,569,786 control chromosomes in the GnomAD database, including 51,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (10445 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40994 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.36

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=-0.8).
• BP6: Variant 8-6409253-G-A is Benign according to our data. Variant chr8-6409253-G-A is described in ClinVar as [Benign]. Clinvar id is 158854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6409253-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.23-26G>A		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.23-26G>A		intron_variant		1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49785 AN: 151902 Hom.: 10413 Cov.: 32

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.251 AC: 62496 AN: 249246 Hom.: 9272 AF XY: 0.246 AC XY: 33213 AN XY: 135260

Gnomad AFR exome AF: 0.614

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.304

Gnomad SAS exome AF: 0.267

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.230 AC: 325397 AN: 1417766 Hom.: 40994 Cov.: 24 AF XY: 0.230 AC XY: 162640 AN XY: 708232

Gnomad4 AFR exome AF: 0.619

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.292

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.328 AC: 49861 AN: 152020 Hom.: 10445 Cov.: 32 AF XY: 0.321 AC XY: 23876 AN XY: 74330

Gnomad4 AFR AF: 0.602

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.315

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.275

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.310

Alfa AF: 0.241 Hom.: 6300

Bravo AF: 0.349

Asia WGS AF: 0.297 AC: 1036 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

- -

Microcephaly 1, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.81
Dann	Benign	0.84

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: rs1550697; hg19: chr8-6266774;