rs2253560

chr8-6620960-G-Achr8-6620960-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):c.2215-494G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 191,354 control chromosomes in the GnomAD database, including 4,128 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3571 hom., cov: 32)
  • Exomes 𝑓: 0.16 (557 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.714

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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.2215-494G>A		intron_variant		ENST00000344683.10
MCPH1-AS1	NR_125386.1	n.442+463C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.2215-494G>A		intron_variant		1	NM_024596.5	P1
MCPH1-AS1	ENST00000661193.1	n.1055-736C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29978 AN: 152002 Hom.: 3574 Cov.: 32

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0741

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.159 AC: 6244 AN: 39232 Hom.: 557 Cov.: 0 AF XY: 0.160 AC XY: 3309 AN XY: 20740

Gnomad4 AFR exome AF: 0.0379

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.0492

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.159

GnomAD4 genome AF: 0.197 AC: 29978 AN: 152122 Hom.: 3571 Cov.: 32 AF XY: 0.196 AC XY: 14572 AN XY: 74354

Gnomad4 AFR AF: 0.0718

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.0741

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.251

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.212

Alfa AF: 0.244 Hom.: 2724

Bravo AF: 0.184

Asia WGS AF: 0.159 AC: 554 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.32
Dann	Benign	0.58

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: rs2253560; hg19: chr8-6478481;