rs77959215

chr8-6445071-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_024596.5(MCPH1):c.1349A>C(p.Lys450Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,614,274 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.135

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028072).
• BP6: Variant 8-6445071-A-C is Benign according to our data. Variant chr8-6445071-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 499746.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=2}. Variant chr8-6445071-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00152 (231/152386) while in subpopulation AFR AF= 0.00519 (216/41598). AF 95% confidence interval is 0.00463. There are 1 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.1349A>C	p.Lys450Thr	missense_variant	8/14	ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.1349A>C	p.Lys450Thr	missense_variant	8/14	1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152268 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000293 AC: 73 AN: 249500 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135378

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1461888 Hom.: 2 Cov.: 54 AF XY: 0.000143 AC XY: 104 AN XY: 727246

Gnomad4 AFR exome AF: 0.00502

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152386 Hom.: 1 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74526

Gnomad4 AFR AF: 0.00519

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.00170

ESP6500AA AF: 0.00504 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000405 AC: 49

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MCPH1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

MCPH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	11
Dann	Uncertain	0.99
DEOGEN2	Benign	0.090	T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.050	N
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.020	B;.;.
Vest4		0.091
MVP		0.25
ClinPred		0.012	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.21

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: rs77959215; hg19: chr8-6302592;