rs2305023

chr8-6406609-G-C

Variant summary

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

The ENST00000519480.6(MCPH1):c.-59G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,590,766 control chromosomes in the GnomAD database, including 448,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33640 hom., cov: 34)
  • Exomes 𝑓: 0.75 (414660 hom.)
• Consequence: MCPH1 ENST00000519480.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.357

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-DT (HGNC:55599): (MCPH1 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-6406609-G-C is Benign according to our data. Variant chr8-6406609-G-C is described in ClinVar as [Benign]. Clinvar id is 363515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5			upstream_gene_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10			upstream_gene_variant		1	NM_024596.5	P1
MCPH1-DT	ENST00000500118.4			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.638 AC: 97008 AN: 151938 Hom.: 33638 Cov.: 34

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.792

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.753 AC: 1083070 AN: 1438710 Hom.: 414660 Cov.: 31 AF XY: 0.751 AC XY: 536670 AN XY: 714296

Gnomad4 AFR exome AF: 0.367

Gnomad4 AMR exome AF: 0.543

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.489

Gnomad4 SAS exome AF: 0.625

Gnomad4 FIN exome AF: 0.810

Gnomad4 NFE exome AF: 0.792

Gnomad4 OTH exome AF: 0.719

GnomAD4 genome AF: 0.638 AC: 97040 AN: 152056 Hom.: 33640 Cov.: 34 AF XY: 0.635 AC XY: 47213 AN XY: 74322

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.589

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.478

Gnomad4 SAS AF: 0.622

Gnomad4 FIN AF: 0.792

Gnomad4 NFE AF: 0.792

Gnomad4 OTH AF: 0.645

Alfa AF: 0.705 Hom.: 4944

Bravo AF: 0.613

Asia WGS AF: 0.568 AC: 1974 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary Microcephaly, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.3
Dann	Benign	0.59

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: rs2305023; hg19: chr8-6264130; COSMIC: COSV60911521; COSMIC: COSV60911521;