8-6596265-G-A

Variant names:

• chr8-6596265-G-A
• rs4841333
• NM_024596.5:c.2215-25189G>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.2215-25189G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,100 control chromosomes in the GnomAD database, including 5,492 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 0.26 (5492 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.402
• Publications: 4 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 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000297646 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.313 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2215-25189G>A		intron	N/A	NP_078872.3
	MCPH1	NM_001322042.2		c.2215-25189G>A		intron	N/A	NP_001308971.2
	MCPH1	NM_001410917.1		c.2215-25189G>A		intron	N/A	NP_001397846.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2215-25189G>A		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000692836.1		c.2215-25189G>A		intron	N/A	ENSP00000509971.1
	MCPH1	ENST00000689348.1		c.2215-25189G>A		intron	N/A	ENSP00000509554.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39236 AN: 151982 Hom.: 5488 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.0611

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.258 AC: 39253 AN: 152100 Hom.: 5492 Cov.: 32 AF XY: 0.258 AC XY: 19198 AN XY: 74354

African (AFR) AF: 0.186 AC: 7706 AN: 41484

American (AMR) AF: 0.199 AC: 3045 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 906 AN: 3470

East Asian (EAS) AF: 0.0611 AC: 316 AN: 5174

South Asian (SAS) AF: 0.326 AC: 1571 AN: 4816

European-Finnish (FIN) AF: 0.348 AC: 3677 AN: 10570

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21140 AN: 67976

Other (OTH) AF: 0.250 AC: 529 AN: 2116

Alfa AF: 0.193 Hom.: 582

Bravo AF: 0.244

Asia WGS AF: 0.216 AC: 754 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.51
PhyloP100		-0.40
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: rs4841333; hg19: chr8-6453786;