Genetic Variant MCPH1:c.-59G>C (chr8-6406609-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_StrongBA1

The ENST00000523225.2(MCPH1-DT):n.161C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,590,766 control chromosomes in the GnomAD database, including 448,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 33640 hom., cov: 34)

Exomes 𝑓: 0.75 ( 414660 hom. )

Consequence

MCPH1-DT
ENST00000523225.2 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.357

Publications

14 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 links:

MCPH1-DT (HGNC:55599): (MCPH1 divergent transcript)

MCPH1-DT 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 (BayesDel_noAF=-0.8).

BP6

Variant 8-6406609-G-C is Benign according to our data. Variant chr8-6406609-G-C is described in ClinVar as [Benign]. Clinvar id is 363515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.-59G>C		upstream_gene_variant		ENST00000344683.10	NP_078872.3	Q8NEM0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 link	c.-59G>C		upstream_gene_variant		1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.638

AC:

97008

AN:

151938

Hom.:

33638

Cov.:

show subpopulations

Gnomad AFR

AF:

0.375

Gnomad AMI

AF:

0.939

Gnomad AMR

AF:

0.589

Gnomad ASJ

AF:

0.688

Gnomad EAS

AF:

0.479

Gnomad SAS

AF:

0.623

Gnomad FIN

AF:

0.792

Gnomad MID

AF:

0.662

Gnomad NFE

AF:

0.792

Gnomad OTH

AF:

0.644

GnomAD4 exome

AF:

0.753

AC:

1083070

AN:

1438710

Hom.:

414660

Cov.:

AF XY:

0.751

AC XY:

536670

AN XY:

714296

show subpopulations

African (AFR)

AF:

0.367

AC:

11972

AN:

32618

American (AMR)

AF:

0.543

AC:

22764

AN:

41894

Ashkenazi Jewish (ASJ)

AF:

0.690

AC:

17579

AN:

25486

East Asian (EAS)

AF:

0.489

AC:

18956

AN:

38786

South Asian (SAS)

AF:

0.625

AC:

52394

AN:

83788

European-Finnish (FIN)

AF:

0.810

AC:

40770

AN:

50326

Middle Eastern (MID)

AF:

0.656

AC:

3515

AN:

5358

European-Non Finnish (NFE)

AF:

0.792

AC:

872393

AN:

1101068

Other (OTH)

AF:

0.719

AC:

42727

AN:

59386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

13109

26218

39327

52436

65545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.638

AC:

97040

AN:

152056

Hom.:

33640

Cov.:

AF XY:

0.635

AC XY:

47213

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.375

AC:

15571

AN:

41500

American (AMR)

AF:

0.589

AC:

8996

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.688

AC:

2390

AN:

3472

East Asian (EAS)

AF:

0.478

AC:

2445

AN:

5110

South Asian (SAS)

AF:

0.622

AC:

3000

AN:

4824

European-Finnish (FIN)

AF:

0.792

AC:

8406

AN:

10614

Middle Eastern (MID)

AF:

0.651

AC:

190

AN:

292

European-Non Finnish (NFE)

AF:

0.792

AC:

53824

AN:

67938

Other (OTH)

AF:

0.645

AC:

1362

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1579

3159

4738

6318

7897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.705

Hom.:

4944

Bravo

AF:

0.613

Asia WGS

AF:

0.568

AC:

1974

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary Microcephaly, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

-0.80

CADD

Benign

5.3

(source)

DANN

Benign

0.59

PhyloP100

-0.36

PromoterAI

0.048

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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.

chr8-6406609-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over