rs146586991

chr8-6445217-G-Achr8-6445217-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024596.5(MCPH1):c.1495G>A(p.Val499Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,614,256 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -3.06

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025476217).
• BP6: Variant 8-6445217-G-A is Benign according to our data. Variant chr8-6445217-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96129.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0033 (503/152364) while in subpopulation AFR AF= 0.0112 (466/41578). AF 95% confidence interval is 0.0104. There are 5 homozygotes in gnomad4. There are 247 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.1495G>A	p.Val499Met	missense_variant	8/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.1495G>A	p.Val499Met	missense_variant	8/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152248 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000846 AC: 211 AN: 249458 Hom.: 2 AF XY: 0.000702 AC XY: 95 AN XY: 135354

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000354 AC: 518 AN: 1461892 Hom.: 3 Cov.: 46 AF XY: 0.000314 AC XY: 228 AN XY: 727248

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.00330 AC: 503 AN: 152364 Hom.: 5 Cov.: 33 AF XY: 0.00332 AC XY: 247 AN XY: 74508

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000635 Hom.: 1

Bravo AF: 0.00375

ESP6500AA AF: 0.00892 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00106 AC: 128

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 10, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 27, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.0020
Dann	Benign	0.66
DEOGEN2	Benign	0.052	T;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0023	N
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.018
Sift	Benign	0.074	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.25	B;.;.
Vest4		0.040
MVP		0.095
ClinPred		0.0062	T
GERP RS		-11
Varity_R		0.020
gMVP		0.082

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: rs146586991; hg19: chr8-6302738; COSMIC: COSV60914007;