8-6439029-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024596.5(MCPH1):c.513G>T(p.Arg171Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.973 in 1,612,852 control chromosomes in the GnomAD database, including 765,580 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.93 (65878 hom., cov: 31)
  • Exomes 𝑓: 0.98 (699702 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.351

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: Computational evidence support a benign effect (MetaRNN=8.9428073E-7).
• BP6: Variant 8-6439029-G-T is Benign according to our data. Variant chr8-6439029-G-T is described in ClinVar as [Benign]. Clinvar id is 1174812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6439029-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.513G>T	p.Arg171Ser	missense_variant	6/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.513G>T	p.Arg171Ser	missense_variant	6/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.927 AC: 140850 AN: 152020 Hom.: 65849 Cov.: 31

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.957

Gnomad AMR AF: 0.966

Gnomad ASJ AF: 0.977

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.954

Gnomad FIN AF: 0.987

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.947

GnomAD3 exomes AF: 0.969 AC: 241414 AN: 249192 Hom.: 117292 AF XY: 0.970 AC XY: 131250 AN XY: 135246

Gnomad AFR exome AF: 0.771

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.980

Gnomad EAS exome AF: 0.989

Gnomad SAS exome AF: 0.955

Gnomad FIN exome AF: 0.989

Gnomad NFE exome AF: 0.987

Gnomad OTH exome AF: 0.978

GnomAD4 exome AF: 0.978 AC: 1428796 AN: 1460714 Hom.: 699702 Cov.: 36 AF XY: 0.978 AC XY: 710733 AN XY: 726782

Gnomad4 AFR exome AF: 0.766

Gnomad4 AMR exome AF: 0.982

Gnomad4 ASJ exome AF: 0.981

Gnomad4 EAS exome AF: 0.993

Gnomad4 SAS exome AF: 0.955

Gnomad4 FIN exome AF: 0.989

Gnomad4 NFE exome AF: 0.986

Gnomad4 OTH exome AF: 0.967

GnomAD4 genome AF: 0.926 AC: 140932 AN: 152138 Hom.: 65878 Cov.: 31 AF XY: 0.928 AC XY: 69018 AN XY: 74392

Gnomad4 AFR AF: 0.782

Gnomad4 AMR AF: 0.966

Gnomad4 ASJ AF: 0.977

Gnomad4 EAS AF: 0.988

Gnomad4 SAS AF: 0.954

Gnomad4 FIN AF: 0.987

Gnomad4 NFE AF: 0.985

Gnomad4 OTH AF: 0.947

Alfa AF: 0.973 Hom.: 125948

Bravo AF: 0.918

TwinsUK AF: 0.985 AC: 3651

ALSPAC AF: 0.981 AC: 3782

ESP6500AA AF: 0.797 AC: 2997

ESP6500EA AF: 0.983 AC: 8080

ExAC AF: 0.966 AC: 116695

Asia WGS AF: 0.953 AC: 3314 AN: 3478

EpiCase AF: 0.984

EpiControl AF: 0.986

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Microcephaly 1, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.32
Dann	Benign	0.44
DEOGEN2	Benign	0.079	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0020	N
MetaRNN	Benign	8.9e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.013
Sift	Benign	0.86	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.0	B;.
Vest4		0.043
MutPred		0.28		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
ClinPred		0.0013	T
GERP RS		-4.6
Varity_R		0.11
gMVP		0.10

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: rs2442513; hg19: chr8-6296550;