Genetic Variant NM_024596.5:c.305G>C (chr8-6431570-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024596.5(MCPH1):c.305G>C(p.Ser102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,609,642 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S102R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

MCPH1
NM_024596.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.282

Publications

6 publications found

Variant links:

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

MCPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004864216).

BP6

Variant 8-6431570-G-C is Benign according to our data. Variant chr8-6431570-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 158868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (335/151900) while in subpopulation AFR AF = 0.00782 (324/41414). AF 95% confidence interval is 0.00712. There are 4 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MCPH1	NM_024596.5	MANE Select	c.305G>C	p.Ser102Thr	missense	Exon 4 of 14	NP_078872.3
MCPH1	NM_001322042.2		c.305G>C	p.Ser102Thr	missense	Exon 4 of 15	NP_001308971.2
MCPH1	NM_001410917.1		c.305G>C	p.Ser102Thr	missense	Exon 4 of 14	NP_001397846.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.305G>C	p.Ser102Thr	missense	Exon 4 of 14	ENSP00000342924.5
MCPH1	ENST00000519480.6	TSL:1	c.305G>C	p.Ser102Thr	missense	Exon 4 of 8	ENSP00000430962.1
MCPH1	ENST00000692836.1		c.305G>C	p.Ser102Thr	missense	Exon 4 of 13	ENSP00000509971.1

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

335

AN:

151782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00785

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000537

AC:

133

AN:

247560

AF XY:

0.000410

show subpopulations

Gnomad AFR exome

AF:

0.00825

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000215

AC:

313

AN:

1457742

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

125

AN XY:

725164

show subpopulations

African (AFR)

AF:

0.00815

AC:

272

AN:

33364

American (AMR)

AF:

0.000225

AC:

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

85524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109340

Other (OTH)

AF:

0.000481

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00221

AC:

335

AN:

151900

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.00782

AC:

324

AN:

41414

American (AMR)

AF:

0.000525

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67972

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.00254

ESP6500AA

AF:

0.00743

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000588

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Aug 31, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 09, 2018

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MCPH1-related disorder

Benign:1

Apr 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.32

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.065

M_CAP

Benign

0.0049

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

0.28

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.1

REVEL

Benign

0.022

Sift

Benign

0.10

Sift4G

Benign

0.67

Polyphen

0.99

Vest4

0.14

MVP

0.43

ClinPred

0.0087

GERP RS

-0.079

Varity_R

0.054

gMVP

0.22

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over