8-6406744-C-G

Variant summary

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

The NM_024596.5(MCPH1):c.22+55C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,598,048 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (144 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.94

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-6406744-C-G is Benign according to our data. Variant chr8-6406744-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1180214.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00831 (1265/152238) while in subpopulation NFE AF= 0.0136 (925/67984). AF 95% confidence interval is 0.0129. There are 6 homozygotes in gnomad4. There are 557 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.22+55C>G		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.22+55C>G		intron_variant		1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1266 AN: 152128 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00225

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00968

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.00812

GnomAD4 exome AF: 0.0124 AC: 17963 AN: 1445810 Hom.: 144 Cov.: 29 AF XY: 0.0121 AC XY: 8721 AN XY: 719214

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00671

Gnomad4 ASJ exome AF: 0.00101

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.00471

Gnomad4 NFE exome AF: 0.0150

Gnomad4 OTH exome AF: 0.00969

GnomAD4 genome AF: 0.00831 AC: 1265 AN: 152238 Hom.: 6 Cov.: 32 AF XY: 0.00748 AC XY: 557 AN XY: 74422

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00967

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0101 Hom.: 2

Bravo AF: 0.00852

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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

Apr 16, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.62
Dann	Benign	0.28

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: rs140026083; hg19: chr8-6264265;