8-6643040-G-T

Variant names:

• chr8-6643040-G-T
• rs34009706
• NM_024596.5:c.2499G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024596.5(MCPH1):​c.2499G>T​(p.Leu833Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,613,930 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L833L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.15
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16672987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2499G>T	p.Leu833Phe	missense_variant	Exon 14 of 14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2499G>T	p.Leu833Phe	missense_variant	Exon 14 of 14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 30 AN: 249360 AF XY: 0.000118

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000259 AC: 378 AN: 1461646 Hom.: 1 Cov.: 31 AF XY: 0.000241 AC XY: 175 AN XY: 727130

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000301 AC: 335 AN: 1111848

Other (OTH) AF: 0.000695 AC: 42 AN: 60392

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74470

African (AFR) AF: 0.000120 AC: 5 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000507 AC: 2

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.0000910 AC: 11

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive Uncertain:2

Mar 04, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Uncertain:1

May 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2499G>T (p.L833F) alteration is located in exon 14 (coding exon 14) of the MCPH1 gene. This alteration results from a G to T substitution at nucleotide position 2499, causing the leucine (L) at amino acid position 833 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jul 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 833 of the MCPH1 protein (p.Leu833Phe). This variant is present in population databases (rs34009706, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MCPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 158866). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.096	N
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.30
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.30
MutPred		0.30		Loss of sheet (P = 0.1158);
MVP		0.83
ClinPred		0.080	T
GERP RS		0.54
Varity_R		0.16
gMVP		0.33
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs34009706; hg19: chr8-6500561;