8-6469227-C-T

Variant names:

• chr8-6469227-C-T
• rs2442497
• NM_024596.5:c.1936-8367C>T

Variant summary

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

The NM_024596.5(MCPH1):​c.1936-8367C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 152,132 control chromosomes in the GnomAD database, including 53,640 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 0.84 (53640 hom., cov: 31)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.574
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.858 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.1936-8367C>T		intron	N/A	NP_078872.3
	MCPH1	NM_001322042.2		c.1936-8367C>T		intron	N/A	NP_001308971.2
	MCPH1	NM_001410917.1		c.1936-8367C>T		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.1936-8367C>T		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000692836.1		c.1936-8367C>T		intron	N/A	ENSP00000509971.1
	MCPH1	ENST00000689348.1		c.1936-8367C>T		intron	N/A	ENSP00000509554.1

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127412 AN: 152014 Hom.: 53600 Cov.: 31

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.823

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

GnomAD4 genome AF: 0.838 AC: 127510 AN: 152132 Hom.: 53640 Cov.: 31 AF XY: 0.841 AC XY: 62601 AN XY: 74402

African (AFR) AF: 0.779 AC: 32293 AN: 41472

American (AMR) AF: 0.870 AC: 13301 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2691 AN: 3470

East Asian (EAS) AF: 0.828 AC: 4286 AN: 5174

South Asian (SAS) AF: 0.802 AC: 3864 AN: 4816

European-Finnish (FIN) AF: 0.934 AC: 9908 AN: 10610

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58373 AN: 67994

Other (OTH) AF: 0.824 AC: 1737 AN: 2108

Alfa AF: 0.838 Hom.: 5130

Bravo AF: 0.834

Asia WGS AF: 0.819 AC: 2847 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.38
DANN	Benign	0.26
PhyloP100		-0.57
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: rs2442497; hg19: chr8-6326748;