chr8-6642723-C-T

Position:

• chr8-6642723-C-T

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.2453-271C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 506,872 control chromosomes in the GnomAD database, including 4,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1642 hom., cov: 32)
  • Exomes 𝑓: 0.12 (3042 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0410

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-6642723-C-T is Benign according to our data. Variant chr8-6642723-C-T is described in ClinVar as [Benign]. Clinvar id is 1227819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2453-271C>T		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2453-271C>T		intron_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21403 AN: 152006 Hom.: 1638 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.125 AC: 44206 AN: 354748 Hom.: 3042 Cov.: 0 AF XY: 0.127 AC XY: 24052 AN XY: 189140

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.0971

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.0906

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.141 AC: 21437 AN: 152124 Hom.: 1642 Cov.: 32 AF XY: 0.141 AC XY: 10484 AN XY: 74374

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.0896

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.150

Alfa AF: 0.115 Hom.: 993

Bravo AF: 0.146

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	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.47

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: rs2433148; hg19: chr8-6500244;