chr8-6433964-C-T

Variant names:

• chr8-6433964-C-T
• rs2442518
• NM_024596.5:c.322-2084C>T

Variant summary

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

The NM_001322042.2(MCPH1):​c.322-2084C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 151,998 control chromosomes in the GnomAD database, including 38,109 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 0.67 (38109 hom., cov: 30)
• Consequence: MCPH1 NM_001322042.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• 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 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322042.2. 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.322-2084C>T		intron	N/A	NP_078872.3
	MCPH1	NM_001322042.2		c.322-2084C>T		intron	N/A	NP_001308971.2
	MCPH1	NM_001410917.1		c.322-2084C>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.322-2084C>T		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000519480.6	TSL:1	c.322-2084C>T		intron	N/A	ENSP00000430962.1
	MCPH1	ENST00000692836.1		c.322-2084C>T		intron	N/A	ENSP00000509971.1

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101591 AN: 151880 Hom.: 38104 Cov.: 30

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.810

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.685

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

GnomAD4 genome AF: 0.668 AC: 101608 AN: 151998 Hom.: 38109 Cov.: 30 AF XY: 0.677 AC XY: 50283 AN XY: 74310

African (AFR) AF: 0.296 AC: 12247 AN: 41426

American (AMR) AF: 0.788 AC: 12041 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2433 AN: 3468

East Asian (EAS) AF: 0.810 AC: 4171 AN: 5150

South Asian (SAS) AF: 0.751 AC: 3607 AN: 4802

European-Finnish (FIN) AF: 0.880 AC: 9323 AN: 10590

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55385 AN: 67974

Other (OTH) AF: 0.686 AC: 1443 AN: 2102

Alfa AF: 0.774 Hom.: 23617

Bravo AF: 0.647

Asia WGS AF: 0.760 AC: 2639 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.80
PhyloP100		0.014
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: rs2442518; hg19: chr8-6291485;