Genetic Variant MCPH1:c.2214+14026C>G (chr8-6513955-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_024596.5(MCPH1):c.2214+14026C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,052,964 control chromosomes in the GnomAD database, including 8 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 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 8 hom. )

Consequence

MCPH1
NM_024596.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00600

Publications

9 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:

ANGPT2 (HGNC:485): (angiopoietin 2) This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]

ANGPT2 Gene-Disease associations (from GenCC):

lymphatic malformation 10
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ANGPT2 links:

Genome browser will be placed here

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=-0.87).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00174 (264/152156) while in subpopulation NFE AF = 0.00316 (215/67984). AF 95% confidence interval is 0.00282. There are 0 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.2214+14026C>G		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3	Q8NEM0-1
ANGPT2	NM_001118887.2 link	c.1030-111G>C		intron_variant	Intron 6 of 8	ENST00000629816.3	NP_001112359.1	O15123-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 link	c.2214+14026C>G		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1
ANGPT2	ENST00000629816.3 link	c.1030-111G>C		intron_variant	Intron 6 of 8	1	NM_001118887.2	ENSP00000486858.2		O15123-3

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

264

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000757

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.00143

GnomAD4 exome

AF:

0.00263

AC:

2373

AN:

900808

Hom.:

AF XY:

0.00259

AC XY:

1168

AN XY:

451558

show subpopulations

African (AFR)

AF:

0.000204

AC:

AN:

19574

American (AMR)

AF:

0.000908

AC:

AN:

20914

Ashkenazi Jewish (ASJ)

AF:

0.000181

AC:

AN:

16540

East Asian (EAS)

AF:

0.00

AC:

AN:

32506

South Asian (SAS)

AF:

0.0000616

AC:

AN:

48714

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

41498

Middle Eastern (MID)

AF:

0.00159

AC:

AN:

3776

European-Non Finnish (NFE)

AF:

0.00322

AC:

2180

AN:

676828

Other (OTH)

AF:

0.00272

AC:

110

AN:

40458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

117

233

350

466

583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00174

AC:

264

AN:

152156

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41526

American (AMR)

AF:

0.00124

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000757

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00316

AC:

215

AN:

67984

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000358

Hom.:

2050

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.4

(source)

DANN

Benign

0.46

PhyloP100

0.0060

Mutation Taster

=100/0

polymorphism

(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