8-6621521-C-T

Variant names:

• chr8-6621521-C-T
• rs1057090
• NM_024596.5:c.2282C>T

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.2282C>T​(p.Ala761Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 1,613,234 control chromosomes in the GnomAD database, including 143,781 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A761G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.43 (14463 hom., cov: 33)
  • Exomes 𝑓: 0.42 (129318 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.503
• Publications: 46 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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4113652E-6).
• BP6: Variant 8-6621521-C-T is Benign according to our data. Variant chr8-6621521-C-T is described in ClinVar as Benign. ClinVar VariationId is 21702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. 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.2282C>T	p.Ala761Val	missense	Exon 13 of 14	NP_078872.3
	MCPH1	NM_001322042.2		c.2282C>T	p.Ala761Val	missense	Exon 13 of 15	NP_001308971.2
	MCPH1	NM_001410917.1		c.2282C>T	p.Ala761Val	missense	Exon 13 of 14	NP_001397846.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2282C>T	p.Ala761Val	missense	Exon 13 of 14	ENSP00000342924.5
	MCPH1	ENST00000692836.1		c.2282C>T	p.Ala761Val	missense	Exon 13 of 13	ENSP00000509971.1
	MCPH1	ENST00000689348.1		c.2282C>T	p.Ala761Val	missense	Exon 13 of 15	ENSP00000509554.1

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65663 AN: 151916 Hom.: 14441 Cov.: 33

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.432

GnomAD2 exomes AF: 0.433 AC: 108048 AN: 249372 AF XY: 0.434

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.339

Gnomad EAS exome AF: 0.662

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.401

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.417 AC: 609561 AN: 1461200 Hom.: 129318 Cov.: 52 AF XY: 0.419 AC XY: 304878 AN XY: 726940

African (AFR) AF: 0.477 AC: 15954 AN: 33464

American (AMR) AF: 0.397 AC: 17743 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 8781 AN: 26136

East Asian (EAS) AF: 0.676 AC: 26842 AN: 39700

South Asian (SAS) AF: 0.496 AC: 42757 AN: 86254

European-Finnish (FIN) AF: 0.417 AC: 22262 AN: 53376

Middle Eastern (MID) AF: 0.416 AC: 2398 AN: 5768

European-Non Finnish (NFE) AF: 0.403 AC: 447739 AN: 1111418

Other (OTH) AF: 0.416 AC: 25085 AN: 60368

GnomAD4 genome AF: 0.432 AC: 65728 AN: 152034 Hom.: 14463 Cov.: 33 AF XY: 0.436 AC XY: 32366 AN XY: 74304

African (AFR) AF: 0.470 AC: 19492 AN: 41484

American (AMR) AF: 0.393 AC: 5998 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1189 AN: 3470

East Asian (EAS) AF: 0.672 AC: 3468 AN: 5162

South Asian (SAS) AF: 0.494 AC: 2381 AN: 4824

European-Finnish (FIN) AF: 0.408 AC: 4311 AN: 10558

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27574 AN: 67944

Other (OTH) AF: 0.431 AC: 910 AN: 2110

Alfa AF: 0.415 Hom.: 62238

Bravo AF: 0.433

TwinsUK AF: 0.382 AC: 1416

ALSPAC AF: 0.394 AC: 1517

ESP6500AA AF: 0.444 AC: 1888

ESP6500EA AF: 0.392 AC: 3316

ExAC AF: 0.436 AC: 52750

Asia WGS AF: 0.530 AC: 1846 AN: 3478

EpiCase AF: 0.399

EpiControl AF: 0.395

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive Benign:4 Other:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not specified Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18204051)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.18
DANN	Benign	0.70
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0056	N
MetaRNN	Benign	0.0000034	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.50
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.011
ClinPred		0.0058	T
GERP RS		-8.3
Varity_R		0.031
gMVP		0.26
Mutation Taster		=97/3	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: rs1057090; hg19: chr8-6479042; COSMIC: COSV60910792; COSMIC: COSV60910792;