NM_024596.5:c.513G>T

Variant names:

• chr8-6439029-G-T
• rs2442513
• NM_024596.5:c.513G>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:5
• Conservation: PhyloP100: -0.351
• Publications: 38 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 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1174812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.513G>T	p.Arg171Ser	missense	Exon 6 of 14	NP_078872.3
	MCPH1	NM_001322042.2		c.513G>T	p.Arg171Ser	missense	Exon 6 of 15	NP_001308971.2
	MCPH1	NM_001410917.1		c.513G>T	p.Arg171Ser	missense	Exon 6 of 14	NP_001397846.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.513G>T	p.Arg171Ser	missense	Exon 6 of 14	ENSP00000342924.5
	MCPH1	ENST00000519480.6	TSL:1	c.513G>T	p.Arg171Ser	missense	Exon 6 of 8	ENSP00000430962.1
	MCPH1	ENST00000692836.1		c.513G>T	p.Arg171Ser	missense	Exon 6 of 13	ENSP00000509971.1

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

GnomAD2 exomes AF: 0.969 AC: 241414 AN: 249192 AF XY: 0.970

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 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

African (AFR) AF: 0.766 AC: 25640 AN: 33456

American (AMR) AF: 0.982 AC: 43917 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.981 AC: 25620 AN: 26126

East Asian (EAS) AF: 0.993 AC: 39383 AN: 39660

South Asian (SAS) AF: 0.955 AC: 82323 AN: 86230

European-Finnish (FIN) AF: 0.989 AC: 52561 AN: 53168

Middle Eastern (MID) AF: 0.971 AC: 5595 AN: 5762

European-Non Finnish (NFE) AF: 0.986 AC: 1095379 AN: 1111230

Other (OTH) AF: 0.967 AC: 58378 AN: 60360

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

African (AFR) AF: 0.782 AC: 32396 AN: 41416

American (AMR) AF: 0.966 AC: 14772 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.977 AC: 3393 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5118 AN: 5180

South Asian (SAS) AF: 0.954 AC: 4593 AN: 4814

European-Finnish (FIN) AF: 0.987 AC: 10482 AN: 10620

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 67032 AN: 68026

Other (OTH) AF: 0.947 AC: 1999 AN: 2110

Alfa AF: 0.966 Hom.: 261681

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Microcephaly 1, primary, autosomal recessive Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-0.35
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.013
Sift	Benign	0.86	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.043
MutPred		0.28		Gain of relative solvent accessibility (P = 0.0166)
ClinPred		0.0013	T
GERP RS		-4.6
Varity_R		0.11
gMVP		0.10
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2442513; hg19: chr8-6296550; COSMIC: COSV107433838;