8-6434037-C-T

Variant names:

• chr8-6434037-C-T
• rs2442516
• NM_024596.5:c.322-2011C>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.322-2011C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 152,024 control chromosomes in the GnomAD database, including 37,971 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 (37971 hom., cov: 31)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.650
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.322-2011C>T		intron_variant	Intron 4 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.322-2011C>T		intron_variant	Intron 4 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101435 AN: 151906 Hom.: 37966 Cov.: 31

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.854

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.682

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

GnomAD4 genome AF: 0.667 AC: 101452 AN: 152024 Hom.: 37971 Cov.: 31 AF XY: 0.675 AC XY: 50188 AN XY: 74312

African (AFR) AF: 0.296 AC: 12259 AN: 41428

American (AMR) AF: 0.788 AC: 12025 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 2434 AN: 3472

East Asian (EAS) AF: 0.781 AC: 4042 AN: 5178

South Asian (SAS) AF: 0.749 AC: 3606 AN: 4816

European-Finnish (FIN) AF: 0.880 AC: 9296 AN: 10562

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

European-Non Finnish (NFE) AF: 0.815 AC: 55387 AN: 67988

Other (OTH) AF: 0.684 AC: 1446 AN: 2114

Alfa AF: 0.635 Hom.: 2499

Bravo AF: 0.646

Asia WGS AF: 0.744 AC: 2584 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.52
PhyloP100		-0.65
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: rs2442516; hg19: chr8-6291558;