NM_024596.5:c.23-15A>G

Variant names:

• chr8-6409264-A-G
• rs146351889
• NM_024596.5:c.23-15A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024596.5(MCPH1):​c.23-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,594,366 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 32)
  • Exomes 𝑓: 0.013 (163 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00900

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 8-6409264-A-G is Benign according to our data. Variant chr8-6409264-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 158853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6409264-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2140/152300) while in subpopulation AFR AF= 0.0202 (838/41562). AF 95% confidence interval is 0.019. There are 23 homozygotes in gnomad4. There are 998 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.23-15A>G		intron_variant	Intron 1 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.23-15A>G		intron_variant	Intron 1 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2138 AN: 152182 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.0100 AC: 2501 AN: 249494 Hom.: 22 AF XY: 0.00991 AC XY: 1342 AN XY: 135382

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00588

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00582

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0126 AC: 18114 AN: 1442066 Hom.: 163 Cov.: 28 AF XY: 0.0126 AC XY: 9026 AN XY: 718892

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.00651

Gnomad4 ASJ exome AF: 0.00500

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00609

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0141 AC: 2140 AN: 152300 Hom.: 23 Cov.: 32 AF XY: 0.0134 AC XY: 998 AN XY: 74472

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0135 Hom.: 3

Bravo AF: 0.0143

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 21, 2013

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2017

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. -

Oct 03, 2012

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Microcephaly 1, primary, autosomal recessive Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.1
DANN	Benign	0.91
BranchPoint Hunter		4.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs146351889; hg19: chr8-6266785;