rs2277136

Positions:

• chr8-6477687-T-C

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.209

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]

ACMG classification

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/exons	MANE	UniProt
MCPH1	NM_024596.5	c.1973+56T>C		intron_variant		ENST00000344683.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.1973+56T>C		intron_variant		1	NM_024596.5	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19592 AN: 152140 Hom.: 1367 Cov.: 33

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

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.: 33 AF XY: 0.127 AC XY: 9440 AN XY: 74462

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Other links and lift over

dbSNP: rs2277136; hg19: chr8-6335208;