rs2433148

chr8-6642723-C-Achr8-6642723-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024596.5(MCPH1):c.2453-271C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 507,330 control chromosomes in the GnomAD database, including 52 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 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (9 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0410

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-6642723-C-A is Benign according to our data. Variant chr8-6642723-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1219303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1940/152158) while in subpopulation AFR AF= 0.0442 (1832/41494). AF 95% confidence interval is 0.0425. There are 43 homozygotes in gnomad4. There are 924 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.2453-271C>A		intron_variant		ENST00000344683.10
MCPH1-AS1	NR_125386.1	n.70-15413G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.2453-271C>A		intron_variant		1	NM_024596.5	P1
MCPH1-AS1	ENST00000661193.1	n.70-7304G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1933 AN: 152040 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00180 AC: 641 AN: 355172 Hom.: 9 Cov.: 0 AF XY: 0.00150 AC XY: 284 AN XY: 189376

Gnomad4 AFR exome AF: 0.0417

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.000368

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000450

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.00433

GnomAD4 genome AF: 0.0127 AC: 1940 AN: 152158 Hom.: 43 Cov.: 32 AF XY: 0.0124 AC XY: 924 AN XY: 74396

Gnomad4 AFR AF: 0.0442

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0104

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.45
Dann	Benign	0.52

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: rs2433148; hg19: chr8-6500244;