8-6621496-G-C

Variant names:

• chr8-6621496-G-C
• rs587783737
• NM_024596.5:c.2257G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001322042.2(MCPH1):​c.2257G>C​(p.Gly753Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000359 in 1,614,092 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: MCPH1 NM_001322042.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.75
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322042.2. 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.2257G>C	p.Gly753Arg	missense	Exon 13 of 14	NP_078872.3
	MCPH1	NM_001322042.2		c.2257G>C	p.Gly753Arg	missense	Exon 13 of 15	NP_001308971.2
	MCPH1	NM_001410917.1		c.2257G>C	p.Gly753Arg	missense	Exon 13 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.2257G>C	p.Gly753Arg	missense	Exon 13 of 14	ENSP00000342924.5
	MCPH1	ENST00000692836.1		c.2257G>C	p.Gly753Arg	missense	Exon 13 of 13	ENSP00000509971.1
	MCPH1	ENST00000689348.1		c.2257G>C	p.Gly753Arg	missense	Exon 13 of 15	ENSP00000509554.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000676

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000361 AC: 9 AN: 249352 AF XY: 0.0000296

Gnomad AFR exome AF: 0.000581

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461818 Hom.: 1 Cov.: 49 AF XY: 0.0000193 AC XY: 14 AN XY: 727226

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74434

African (AFR) AF: 0.000674 AC: 28 AN: 41566

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.0000413 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Microcephaly 1, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Benign	0.064	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.45		Loss of methylation at R752 (P = 0.0401)
MVP		0.70
ClinPred		0.27	T
GERP RS		4.5
Varity_R		0.25
gMVP		0.41
Mutation Taster		=91/9	polymorphism

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: rs587783737; hg19: chr8-6479017;