8-6444897-A-G

Variant names:

• chr8-6444897-A-G
• rs2515569
• NM_024596.5:c.1175A>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.1175A>G​(p.Asp392Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,614,206 control chromosomes in the GnomAD database, including 804,919 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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.

• Frequency:
  • Genomes: 𝑓 0.99 (75016 hom., cov: 32)
  • Exomes 𝑓: 1.0 (729903 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.71
• Publications: 34 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 (MetaRNN=1.0807453E-6).
• BP6: Variant 8-6444897-A-G is Benign according to our data. Variant chr8-6444897-A-G is described in ClinVar as Benign. ClinVar VariationId is 96126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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.1175A>G	p.Asp392Gly	missense	Exon 8 of 14	NP_078872.3
	MCPH1	NM_001322042.2		c.1175A>G	p.Asp392Gly	missense	Exon 8 of 15	NP_001308971.2
	MCPH1	NM_001410917.1		c.1175A>G	p.Asp392Gly	missense	Exon 8 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.1175A>G	p.Asp392Gly	missense	Exon 8 of 14	ENSP00000342924.5
	MCPH1	ENST00000519480.6	TSL:1	c.1175A>G	p.Asp392Gly	missense	Exon 8 of 8	ENSP00000430962.1
	MCPH1	ENST00000692836.1		c.1175A>G	p.Asp392Gly	missense	Exon 8 of 13	ENSP00000509971.1

Frequencies

GnomAD3 genomes AF: 0.992 AC: 151041 AN: 152196 Hom.: 74959 Cov.: 32

Gnomad AFR AF: 0.973

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.998 AC: 248903 AN: 249358 AF XY: 0.999

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 0.999 AC: 1460831 AN: 1461892 Hom.: 729903 Cov.: 78 AF XY: 0.999 AC XY: 726805 AN XY: 727246

African (AFR) AF: 0.973 AC: 32586 AN: 33480

American (AMR) AF: 0.999 AC: 44678 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39695 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86252 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53418 AN: 53418

Middle Eastern (MID) AF: 0.999 AC: 5761 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1112000 AN: 1112012

Other (OTH) AF: 0.998 AC: 60305 AN: 60396

GnomAD4 genome AF: 0.992 AC: 151157 AN: 152314 Hom.: 75016 Cov.: 32 AF XY: 0.993 AC XY: 73921 AN XY: 74474

African (AFR) AF: 0.973 AC: 40444 AN: 41556

American (AMR) AF: 0.998 AC: 15279 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68032 AN: 68034

Other (OTH) AF: 0.994 AC: 2101 AN: 2114

Alfa AF: 0.997 Hom.: 190960

Bravo AF: 0.991

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.978 AC: 3938

ESP6500EA AF: 1.00 AC: 8371

ExAC AF: 0.998 AC: 120602

Asia WGS AF: 0.999 AC: 3475 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 20, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Microcephaly 1, primary, autosomal recessive Benign:4

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 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.

Jun 28, 2017

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

not provided Benign:3

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: 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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0040
DANN	Benign	0.32
DEOGEN2	Benign	0.077	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0036	N
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-3.7
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.044
Sift	Benign	0.57	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.031
ClinPred		0.024	T
GERP RS		-12
Varity_R		0.032
gMVP		0.14
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: rs2515569; hg19: chr8-6302418; COSMIC: COSV107433839;