Genetic Variant MCPH1:c.2215-494G>A (chr8-6620960-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024596.5(MCPH1):c.2215-494G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 191,354 control chromosomes in the GnomAD database, including 4,128 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3571 hom., cov: 32)

Exomes 𝑓: 0.16 ( 557 hom. )

Consequence

MCPH1
NM_024596.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.714

Publications

5 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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

MCPH1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.2215-494G>A		intron_variant	Intron 12 of 13	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.2215-494G>A		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29978

AN:

152002

Hom.:

3574

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0719

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.223

Gnomad EAS

AF:

0.0741

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.277

Gnomad OTH

AF:

0.212

GnomAD4 exome

AF:

0.159

AC:

6244

AN:

39232

Hom.:

557

Cov.:

AF XY:

0.160

AC XY:

3309

AN XY:

20740

show subpopulations

African (AFR)

AF:

0.0379

AC:

AN:

660

American (AMR)

AF:

0.134

AC:

440

AN:

3278

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

AN:

786

East Asian (EAS)

AF:

0.0492

AC:

AN:

1950

South Asian (SAS)

AF:

0.154

AC:

825

AN:

5354

European-Finnish (FIN)

AF:

0.141

AC:

190

AN:

1344

Middle Eastern (MID)

AF:

0.147

AC:

AN:

102

European-Non Finnish (NFE)

AF:

0.179

AC:

4254

AN:

23826

Other (OTH)

AF:

0.159

AC:

308

AN:

1932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

207

414

620

827

1034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.197

AC:

29978

AN:

152122

Hom.:

3571

Cov.:

AF XY:

0.196

AC XY:

14572

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0718

AC:

2982

AN:

41512

American (AMR)

AF:

0.163

AC:

2494

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

774

AN:

3468

East Asian (EAS)

AF:

0.0741

AC:

384

AN:

5182

South Asian (SAS)

AF:

0.240

AC:

1153

AN:

4806

European-Finnish (FIN)

AF:

0.251

AC:

2650

AN:

10574

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.277

AC:

18813

AN:

67986

Other (OTH)

AF:

0.212

AC:

447

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1209

2417

3626

4834

6043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.251

Hom.:

4140

Bravo

AF:

0.184

Asia WGS

AF:

0.159

AC:

554

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.32

(source)

DANN

Benign

0.58

PhyloP100

-0.71

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over