chr8-6494837-A-C

Position:

• chr8-6494837-A-C

Variant summary

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

The NM_024596.5(MCPH1):​c.2137-5015A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 152,074 control chromosomes in the GnomAD database, including 35,282 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 0.65 (35282 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.325

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2137-5015A>C		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2137-5015A>C		intron_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98372 AN: 151956 Hom.: 35285 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.570

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.803

Gnomad OTH AF: 0.658

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.647 AC: 98380 AN: 152074 Hom.: 35282 Cov.: 32 AF XY: 0.650 AC XY: 48299 AN XY: 74334

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.723

Gnomad4 ASJ AF: 0.705

Gnomad4 EAS AF: 0.571

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.803

Gnomad4 OTH AF: 0.652

Alfa AF: 0.764 Hom.: 33919

Bravo AF: 0.628

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.75
DANN	Benign	0.62

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: rs1031309; hg19: chr8-6352358;