8-6442011-A-G

Variant names:

• chr8-6442011-A-G
• rs2053618
• NM_024596.5:c.581-56A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024596.5(MCPH1):​c.581-56A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,238,778 control chromosomes in the GnomAD database, including 404,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (40753 hom., cov: 32)
  • Exomes 𝑓: 0.81 (363533 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0930
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-6442011-A-G is Benign according to our data. Variant chr8-6442011-A-G is described in ClinVar as Benign. ClinVar VariationId is 673931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.581-56A>G		intron_variant	Intron 6 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.581-56A>G		intron_variant	Intron 6 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107359 AN: 152020 Hom.: 40742 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.712

GnomAD4 exome AF: 0.814 AC: 884770 AN: 1086640 Hom.: 363533 Cov.: 14 AF XY: 0.814 AC XY: 454157 AN XY: 558192

African (AFR) AF: 0.386 AC: 9969 AN: 25842

American (AMR) AF: 0.860 AC: 37646 AN: 43798

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 16317 AN: 23722

East Asian (EAS) AF: 0.813 AC: 30777 AN: 37860

South Asian (SAS) AF: 0.763 AC: 59575 AN: 78128

European-Finnish (FIN) AF: 0.896 AC: 46498 AN: 51890

Middle Eastern (MID) AF: 0.679 AC: 3440 AN: 5064

European-Non Finnish (NFE) AF: 0.833 AC: 642970 AN: 772332

Other (OTH) AF: 0.783 AC: 37578 AN: 48004

GnomAD4 genome AF: 0.706 AC: 107398 AN: 152138 Hom.: 40753 Cov.: 32 AF XY: 0.713 AC XY: 53060 AN XY: 74382

African (AFR) AF: 0.398 AC: 16507 AN: 41488

American (AMR) AF: 0.803 AC: 12272 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2418 AN: 3466

East Asian (EAS) AF: 0.819 AC: 4243 AN: 5178

South Asian (SAS) AF: 0.754 AC: 3635 AN: 4818

European-Finnish (FIN) AF: 0.893 AC: 9463 AN: 10594

Middle Eastern (MID) AF: 0.671 AC: 196 AN: 292

European-Non Finnish (NFE) AF: 0.829 AC: 56338 AN: 67996

Other (OTH) AF: 0.714 AC: 1508 AN: 2112

Alfa AF: 0.765 Hom.: 6502

Bravo AF: 0.688

Asia WGS AF: 0.769 AC: 2671 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.58
DANN	Benign	0.76
PhyloP100		-0.093
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2053618; hg19: chr8-6299532;