NM_024596.5:c.2452+9365G>A

Variant names:

• chr8-6631056-G-A
• rs3020264
• NM_024596.5:c.2452+9365G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):​c.2452+9365G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 152,076 control chromosomes in the GnomAD database, including 4,481 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 0.24 (4481 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.233
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2452+9365G>A		intron_variant	Intron 13 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2452+9365G>A		intron_variant	Intron 13 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36194 AN: 151958 Hom.: 4479 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.0890

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.241

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

GnomAD4 genome AF: 0.238 AC: 36219 AN: 152076 Hom.: 4481 Cov.: 32 AF XY: 0.237 AC XY: 17601 AN XY: 74312

African (AFR) AF: 0.198 AC: 8209 AN: 41496

American (AMR) AF: 0.181 AC: 2761 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 864 AN: 3470

East Asian (EAS) AF: 0.0892 AC: 461 AN: 5166

South Asian (SAS) AF: 0.233 AC: 1121 AN: 4820

European-Finnish (FIN) AF: 0.282 AC: 2974 AN: 10550

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19087 AN: 67982

Other (OTH) AF: 0.240 AC: 506 AN: 2110

Alfa AF: 0.263 Hom.: 21177

Bravo AF: 0.227

Asia WGS AF: 0.163 AC: 567 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.57
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3020264; hg19: chr8-6488577;