dbSNP rs2277136: MCPH1:c.1973+56T>C (chr8-6477687-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024596.5(MCPH1):c.1973+56T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,477,612 control chromosomes in the GnomAD database, including 13,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1369 hom., cov: 33)

Exomes 𝑓: 0.13 ( 11898 hom. )

Consequence

MCPH1
NM_024596.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.209

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 8-6477687-T-C is Benign according to our data. Variant chr8-6477687-T-C is described in ClinVar as [Benign]. Clinvar id is 1225800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.1973+56T>C		intron_variant	Intron 10 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.1973+56T>C		intron_variant	Intron 10 of 13	1	NM_024596.5	ENSP00000342924.5		Q8NEM0-1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19592

AN:

152140

Hom.:

1367

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.0725

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.172

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.0618

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.152

GnomAD4 exome

AF:

0.130

AC:

171721

AN:

1325354

Hom.:

11898

AF XY:

0.132

AC XY:

88053

AN XY:

666744

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.0963

Gnomad4 ASJ exome

AF:

0.229

Gnomad4 EAS exome

AF:

0.186

Gnomad4 SAS exome

AF:

0.182

Gnomad4 FIN exome

AF:

0.0603

Gnomad4 NFE exome

AF:

0.124

Gnomad4 OTH exome

AF:

0.144

GnomAD4 genome

AF:

0.129

AC:

19600

AN:

152258

Hom.:

1369

Cov.:

AF XY:

0.127

AC XY:

9440

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.128

Gnomad4 AMR

AF:

0.119

Gnomad4 ASJ

AF:

0.216

Gnomad4 EAS

AF:

0.172

Gnomad4 SAS

AF:

0.193

Gnomad4 FIN

AF:

0.0618

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.151

Alfa

AF:

0.127

Hom.:

211

Bravo

AF:

0.130

Asia WGS

AF:

0.167

AC:

582

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 29, 2018

GeneDx

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

-0.86

CADD

Benign

1.0

DANN

Benign

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over