dbSNP rs140026083: MCPH1:c.22+55C>G (chr8-6406744-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_024596.5(MCPH1):c.22+55C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,598,048 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0083 ( 6 hom., cov: 32)

Exomes 𝑓: 0.012 ( 144 hom. )

Consequence

MCPH1
NM_024596.5 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.94

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-6406744-C-G is Benign according to our data. Variant chr8-6406744-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1180214.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00831 (1265/152238) while in subpopulation NFE AF = 0.0136 (925/67984). AF 95% confidence interval is 0.0129. There are 6 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.22+55C>G		intron_variant	Intron 1 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.22+55C>G		intron_variant	Intron 1 of 13	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.00832

AC:

1266

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00225

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.00968

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0136

Gnomad OTH

AF:

0.00812

GnomAD4 exome

AF:

0.0124

AC:

17963

AN:

1445810

Hom.:

144

Cov.:

AF XY:

0.0121

AC XY:

8721

AN XY:

719214

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

33258

American (AMR)

AF:

0.00671

AC:

295

AN:

43996

Ashkenazi Jewish (ASJ)

AF:

0.00101

AC:

AN:

25804

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39432

South Asian (SAS)

AF:

0.00211

AC:

179

AN:

84742

European-Finnish (FIN)

AF:

0.00471

AC:

244

AN:

51832

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.0150

AC:

16570

AN:

1101268

Other (OTH)

AF:

0.00969

AC:

580

AN:

59832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

900

1799

2699

3598

4498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00831

AC:

1265

AN:

152238

Hom.:

Cov.:

AF XY:

0.00748

AC XY:

557

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41542

American (AMR)

AF:

0.00967

AC:

148

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00166

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0136

AC:

925

AN:

67984

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00852

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 16, 2019

GeneDx

Significance:Likely 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

0.62

(source)

DANN

Benign

0.28

PhyloP100

-3.9

PromoterAI

-0.048

Neutral

(source)

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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rs140026083

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