rs2584

Variant names:

• chr8-6445504-G-A
• rs2584
• NM_024596.5:c.1782G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6445504-G-A
• chr8-6445504-G-C
• chr8-6445504-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024596.5(MCPH1):​c.1782G>A​(p.Thr594Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,610,700 control chromosomes in the GnomAD database, including 81,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5542 hom., cov: 34)
  • Exomes 𝑓: 0.31 (75794 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.75
• Publications: 25 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-6445504-G-A is Benign according to our data. Variant chr8-6445504-G-A is described in ClinVar as Benign. ClinVar VariationId is 158827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1782G>A	p.Thr594Thr	synonymous_variant	Exon 8 of 14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.1782G>A	p.Thr594Thr	synonymous_variant	Exon 8 of 14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36021 AN: 152082 Hom.: 5542 Cov.: 34

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.0264

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.217

GnomAD2 exomes AF: 0.262 AC: 64266 AN: 245124 AF XY: 0.261

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.0227

Gnomad FIN exome AF: 0.357

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.310 AC: 452485 AN: 1458500 Hom.: 75794 Cov.: 40 AF XY: 0.306 AC XY: 221953 AN XY: 725332

African (AFR) AF: 0.0490 AC: 1623 AN: 33110

American (AMR) AF: 0.276 AC: 12183 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5316 AN: 26038

East Asian (EAS) AF: 0.0310 AC: 1232 AN: 39680

South Asian (SAS) AF: 0.139 AC: 11903 AN: 85404

European-Finnish (FIN) AF: 0.362 AC: 19215 AN: 53136

Middle Eastern (MID) AF: 0.155 AC: 889 AN: 5728

European-Non Finnish (NFE) AF: 0.345 AC: 383643 AN: 1111050

Other (OTH) AF: 0.274 AC: 16481 AN: 60198

GnomAD4 genome AF: 0.237 AC: 36023 AN: 152200 Hom.: 5542 Cov.: 34 AF XY: 0.233 AC XY: 17318 AN XY: 74404

African (AFR) AF: 0.0613 AC: 2549 AN: 41554

American (AMR) AF: 0.261 AC: 3994 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 787 AN: 3470

East Asian (EAS) AF: 0.0264 AC: 137 AN: 5186

South Asian (SAS) AF: 0.122 AC: 590 AN: 4832

European-Finnish (FIN) AF: 0.357 AC: 3767 AN: 10550

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23374 AN: 67994

Other (OTH) AF: 0.215 AC: 454 AN: 2114

Alfa AF: 0.298 Hom.: 22188

Bravo AF: 0.225

Asia WGS AF: 0.0750 AC: 264 AN: 3478

EpiCase AF: 0.315

EpiControl AF: 0.317

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.43
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2584; hg19: chr8-6303025; COSMIC: COSV60913176;