chr8-6456965-C-T

Variant names:

• chr8-6456965-C-T
• rs2442502
• NM_024596.5:c.1935+1713C>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.1935+1713C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 151,876 control chromosomes in the GnomAD database, including 38,587 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 (38587 hom., cov: 30)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.467
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1935+1713C>T		intron_variant	Intron 9 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.1935+1713C>T		intron_variant	Intron 9 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102382 AN: 151758 Hom.: 38582 Cov.: 30

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.783

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.884

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.822

Gnomad OTH AF: 0.683

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

GnomAD4 genome AF: 0.674 AC: 102400 AN: 151876 Hom.: 38587 Cov.: 30 AF XY: 0.682 AC XY: 50627 AN XY: 74214

African (AFR) AF: 0.304 AC: 12577 AN: 41340

American (AMR) AF: 0.791 AC: 12083 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2436 AN: 3464

East Asian (EAS) AF: 0.784 AC: 4020 AN: 5130

South Asian (SAS) AF: 0.750 AC: 3598 AN: 4796

European-Finnish (FIN) AF: 0.884 AC: 9350 AN: 10572

Middle Eastern (MID) AF: 0.620 AC: 181 AN: 292

European-Non Finnish (NFE) AF: 0.822 AC: 55891 AN: 67992

Other (OTH) AF: 0.685 AC: 1446 AN: 2112

Alfa AF: 0.777 Hom.: 22795

Bravo AF: 0.653

Asia WGS AF: 0.740 AC: 2573 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.48
DANN	Benign	0.36
PhyloP100		-0.47
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: rs2442502; hg19: chr8-6314486;