NM_024596.5:c.*181C>G

Variant names:

• chr8-6643230-C-G
• rs2433149
• NM_024596.5:c.*181C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024596.5(MCPH1):​c.*181C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 664,116 control chromosomes in the GnomAD database, including 33,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7189 hom., cov: 33)
  • Exomes 𝑓: 0.31 (26069 hom.)
• Consequence: MCPH1 NM_024596.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.165
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-6643230-C-G is Benign according to our data. Variant chr8-6643230-C-G is described in ClinVar as Benign. ClinVar VariationId is 363567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.*181C>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.*181C>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46364 AN: 152078 Hom.: 7173 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.315 AC: 161002 AN: 511920 Hom.: 26069 Cov.: 4 AF XY: 0.319 AC XY: 87641 AN XY: 274782

African (AFR) AF: 0.328 AC: 4583 AN: 13982

American (AMR) AF: 0.209 AC: 5646 AN: 27020

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 5472 AN: 17758

East Asian (EAS) AF: 0.286 AC: 9024 AN: 31558

South Asian (SAS) AF: 0.393 AC: 21863 AN: 55630

European-Finnish (FIN) AF: 0.294 AC: 9924 AN: 33804

Middle Eastern (MID) AF: 0.331 AC: 960 AN: 2896

European-Non Finnish (NFE) AF: 0.315 AC: 94842 AN: 300708

Other (OTH) AF: 0.304 AC: 8688 AN: 28564

GnomAD4 genome AF: 0.305 AC: 46420 AN: 152196 Hom.: 7189 Cov.: 33 AF XY: 0.305 AC XY: 22711 AN XY: 74392

African (AFR) AF: 0.323 AC: 13402 AN: 41546

American (AMR) AF: 0.223 AC: 3415 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1100 AN: 3468

East Asian (EAS) AF: 0.222 AC: 1149 AN: 5174

South Asian (SAS) AF: 0.390 AC: 1880 AN: 4824

European-Finnish (FIN) AF: 0.280 AC: 2968 AN: 10588

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.316 AC: 21498 AN: 67984

Other (OTH) AF: 0.306 AC: 645 AN: 2110

Alfa AF: 0.304 Hom.: 931

Bravo AF: 0.298

Asia WGS AF: 0.301 AC: 1049 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly 1, primary, autosomal recessive Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.7
DANN	Benign	0.71
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2433149; hg19: chr8-6500751; COSMIC: COSV60920476;