8-6406587-C-T

Position:

• chr8-6406587-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000523225.1(MCPH1-DT):​n.183G>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 0.0018 in 1,475,276 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0095 (24 hom., cov: 34)
  • Exomes 𝑓: 0.00091 (16 hom.)
• Consequence: MCPH1-DT ENST00000523225.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.723

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 8-6406587-C-T is Benign according to our data. Variant chr8-6406587-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1209160.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00952 (1449/152270) while in subpopulation AFR AF= 0.0312 (1297/41570). AF 95% confidence interval is 0.0298. There are 24 homozygotes in gnomad4. There are 709 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5			upstream_gene_variant		ENST00000344683.10
MCPH1-DT	NR_040040.1			upstream_gene_variant

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: 0.00950 AC: 1446 AN: 152152 Hom.: 24 Cov.: 34

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.000912 AC: 1207 AN: 1323006 Hom.: 16 Cov.: 19 AF XY: 0.000758 AC XY: 499 AN XY: 658288

Gnomad4 AFR exome AF: 0.0294

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000691

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00952 AC: 1449 AN: 152270 Hom.: 24 Cov.: 34 AF XY: 0.00952 AC XY: 709 AN XY: 74436

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00816

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00698 Hom.: 3

Bravo AF: 0.0108

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.9
DANN	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs190692683; hg19: chr8-6264108;