8-6480478-A-G

Variant names:

• chr8-6480478-A-G
• rs13248420
• NM_024596.5:c.1974-236A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024596.5(MCPH1):​c.1974-236A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,240 control chromosomes in the GnomAD database, including 1,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (1785 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.04

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-6480478-A-G is Benign according to our data. Variant chr8-6480478-A-G is described in ClinVar as [Benign]. Clinvar id is 1232017.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1974-236A>G		intron_variant	Intron 10 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.1974-236A>G		intron_variant	Intron 10 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22326 AN: 152122 Hom.: 1783 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.0921

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.170

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.147 AC: 22334 AN: 152240 Hom.: 1785 Cov.: 32 AF XY: 0.144 AC XY: 10702 AN XY: 74436

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.0921

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.169

Alfa AF: 0.0741 Hom.: 96

Bravo AF: 0.147

Asia WGS AF: 0.166 AC: 579 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0010
DANN	Benign	0.51

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: rs13248420; hg19: chr8-6337999;