8-6621205-C-A

Position:

• chr8-6621205-C-A

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.2215-249C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0577 in 551,802 control chromosomes in the GnomAD database, including 1,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (318 hom., cov: 33)
  • Exomes 𝑓: 0.061 (1304 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0810

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=-0.77).
• BP6: Variant 8-6621205-C-A is Benign according to our data. Variant chr8-6621205-C-A is described in ClinVar as [Benign]. Clinvar id is 1242366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2215-249C>A		intron_variant		ENST00000344683.10	NP_078872.3
MCPH1-AS1	NR_125386.1	n.442+218G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2215-249C>A		intron_variant		1	NM_024596.5	ENSP00000342924	P1
MCPH1-AS1	ENST00000661193.1	n.1055-981G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 7382 AN: 152104 Hom.: 321 Cov.: 33

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.0373

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.0788

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0517

Gnomad OTH AF: 0.0512

GnomAD4 exome AF: 0.0612 AC: 24442 AN: 399580 Hom.: 1304 Cov.: 4 AF XY: 0.0619 AC XY: 13110 AN XY: 211914

Gnomad4 AFR exome AF: 0.00956

Gnomad4 AMR exome AF: 0.0630

Gnomad4 ASJ exome AF: 0.0317

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.0666

Gnomad4 FIN exome AF: 0.0630

Gnomad4 NFE exome AF: 0.0491

Gnomad4 OTH exome AF: 0.0496

GnomAD4 genome AF: 0.0485 AC: 7384 AN: 152222 Hom.: 318 Cov.: 33 AF XY: 0.0510 AC XY: 3799 AN XY: 74432

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.0504

Gnomad4 ASJ AF: 0.0373

Gnomad4 EAS AF: 0.244

Gnomad4 SAS AF: 0.0789

Gnomad4 FIN AF: 0.0685

Gnomad4 NFE AF: 0.0517

Gnomad4 OTH AF: 0.0507

Alfa AF: 0.0534 Hom.: 35

Bravo AF: 0.0460

Asia WGS AF: 0.139 AC: 487 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.6
DANN	Benign	0.79

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: rs71525742; hg19: chr8-6478726;