rs2515566

Variant names:

• chr8-6640232-C-G
• rs2515566
• NM_024596.5:c.2453-2762C>G

Variant summary

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

The NM_024596.5(MCPH1):​c.2453-2762C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 152,014 control chromosomes in the GnomAD database, including 3,302 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 0.16 (3302 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.202
• Publications: 2 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2453-2762C>G		intron	N/A	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2595-2762C>G		intron	N/A	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001363980.2		c.2174-2762C>G		intron	N/A	NP_001350909.1	A0A8I5KR97

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2453-2762C>G		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000689348.1		c.2595-2762C>G		intron	N/A	ENSP00000509554.1	A0A8I5KV10
	MCPH1	ENST00000949609.1		c.2375-2762C>G		intron	N/A	ENSP00000619668.1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24769 AN: 151896 Hom.: 3289 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0898

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.163 AC: 24827 AN: 152014 Hom.: 3302 Cov.: 32 AF XY: 0.158 AC XY: 11763 AN XY: 74332

African (AFR) AF: 0.371 AC: 15362 AN: 41386

American (AMR) AF: 0.0896 AC: 1370 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3466

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.102 AC: 491 AN: 4814

European-Finnish (FIN) AF: 0.0433 AC: 458 AN: 10574

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0917 AC: 6234 AN: 67988

Other (OTH) AF: 0.149 AC: 315 AN: 2110

Alfa AF: 0.137 Hom.: 290

Bravo AF: 0.175

Asia WGS AF: 0.0750 AC: 261 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.51
PhyloP100		-0.20
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: rs2515566; hg19: chr8-6497753;