8-6406552-G-T

Position:

• chr8-6406552-G-T

Variant summary

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

The ENST00000500118.4(MCPH1-DT):​n.21C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,140,492 control chromosomes in the GnomAD database, including 1,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (736 hom., cov: 34)
  • Exomes 𝑓: 0.017 (531 hom.)
• Consequence: MCPH1-DT ENST00000500118.4 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.285

Genes affected

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

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=-0.76).
• BP6: Variant 8-6406552-G-T is Benign according to our data. Variant chr8-6406552-G-T is described in ClinVar as [Benign]. Clinvar id is 1247952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1-DT	NR_040040.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1-DT	ENST00000500118.4	n.21C>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0644 AC: 9797 AN: 152124 Hom.: 732 Cov.: 34

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0649

GnomAD4 exome AF: 0.0175 AC: 17276 AN: 988250 Hom.: 531 Cov.: 12 AF XY: 0.0168 AC XY: 8338 AN XY: 497382

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.0272

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0261

GnomAD4 genome AF: 0.0645 AC: 9823 AN: 152242 Hom.: 736 Cov.: 34 AF XY: 0.0644 AC XY: 4793 AN XY: 74428

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.0379

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.0312

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0643

Bravo AF: 0.0697

Asia WGS AF: 0.0170 AC: 61 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.1
DANN	Benign	0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2916655; hg19: chr8-6264073;