rs2433149

chr8-6643230-C-Gchr8-6643230-C-T

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: 0.165

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

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
MCPH1	NM_024596.5	c.*181C>G		3_prime_UTR_variant	14/14	ENST00000344683.10
MCPH1-AS1	NR_125386.1	n.70-15920G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.*181C>G		3_prime_UTR_variant	14/14	1	NM_024596.5	P1
MCPH1-AS1	ENST00000661193.1	n.70-7811G>C		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.328

Gnomad4 AMR exome AF: 0.209

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.294

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.304

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

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.317

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.390

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.306

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 1, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	2.7
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

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