rs2912016

Variant names:

• chr8-6621657-C-A
• rs2912016
• NM_024596.5:c.2418C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6621657-C-A
• chr8-6621657-C-G
• chr8-6621657-C-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.2418C>A​(p.Ala806Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,613,730 control chromosomes in the GnomAD database, including 106,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A806A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.37 (10740 hom., cov: 33)
  • Exomes 𝑓: 0.36 (95947 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.28
• Publications: 27 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-6621657-C-A is Benign according to our data. Variant chr8-6621657-C-A is described in ClinVar as Benign. ClinVar VariationId is 158857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2418C>A	p.Ala806Ala	synonymous_variant	Exon 13 of 14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2418C>A	p.Ala806Ala	synonymous_variant	Exon 13 of 14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56918 AN: 151976 Hom.: 10722 Cov.: 33

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.364 AC: 90860 AN: 249360 AF XY: 0.367

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.361 AC: 527805 AN: 1461636 Hom.: 95947 Cov.: 43 AF XY: 0.363 AC XY: 263955 AN XY: 727124

African (AFR) AF: 0.428 AC: 14328 AN: 33476

American (AMR) AF: 0.319 AC: 14272 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7866 AN: 26134

East Asian (EAS) AF: 0.447 AC: 17753 AN: 39694

South Asian (SAS) AF: 0.427 AC: 36860 AN: 86250

European-Finnish (FIN) AF: 0.372 AC: 19880 AN: 53414

Middle Eastern (MID) AF: 0.400 AC: 2309 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392830 AN: 1111790

Other (OTH) AF: 0.359 AC: 21707 AN: 60390

GnomAD4 genome AF: 0.375 AC: 56973 AN: 152094 Hom.: 10740 Cov.: 33 AF XY: 0.377 AC XY: 28055 AN XY: 74328

African (AFR) AF: 0.421 AC: 17472 AN: 41506

American (AMR) AF: 0.336 AC: 5137 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1065 AN: 3472

East Asian (EAS) AF: 0.430 AC: 2218 AN: 5158

South Asian (SAS) AF: 0.415 AC: 2001 AN: 4822

European-Finnish (FIN) AF: 0.368 AC: 3885 AN: 10562

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24069 AN: 67986

Other (OTH) AF: 0.369 AC: 778 AN: 2110

Alfa AF: 0.352 Hom.: 15268

Bravo AF: 0.373

Asia WGS AF: 0.387 AC: 1344 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Apr 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Microcephaly 1, primary, autosomal recessive Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided Benign:3

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.034
DANN	Benign	0.64
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs2912016; hg19: chr8-6479178; COSMIC: COSV60911550; COSMIC: COSV60911550;