rs35551093

Positions:

• chr8-6445441-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024596.5(MCPH1):​c.1719C>T​(p.Ser573Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,218 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (42 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.267

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-6445441-C-T is Benign according to our data. Variant chr8-6445441-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 158824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-6445441-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.267 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1965/152334) while in subpopulation AFR AF= 0.0441 (1834/41566). AF 95% confidence interval is 0.0424. There are 42 homozygotes in gnomad4. There are 965 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1719C>T	p.Ser573Ser	synonymous_variant	8/14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.1719C>T	p.Ser573Ser	synonymous_variant	8/14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1949 AN: 152216 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00313 AC: 781 AN: 249332 Hom.: 13 AF XY: 0.00248 AC XY: 335 AN XY: 135348

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00140 AC: 2049 AN: 1461884 Hom.: 35 Cov.: 45 AF XY: 0.00121 AC XY: 883 AN XY: 727240

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.0129 AC: 1965 AN: 152334 Hom.: 42 Cov.: 33 AF XY: 0.0130 AC XY: 965 AN XY: 74498

Gnomad4 AFR AF: 0.0441

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00539 Hom.: 9

Bravo AF: 0.0139

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 16, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephaly 1, primary, autosomal recessive Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 01, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.46

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: rs35551093; hg19: chr8-6302962;