8-6480478-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.1974-236A>G		intron	N/A	NP_078872.3
	MCPH1	NM_001322042.2		c.1974-236A>G		intron	N/A	NP_001308971.2
	MCPH1	NM_001410917.1		c.1974-236A>G		intron	N/A	NP_001397846.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.1974-236A>G		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000692836.1		c.1974-236A>G		intron	N/A	ENSP00000509971.1
	MCPH1	ENST00000689348.1		c.1974-236A>G		intron	N/A	ENSP00000509554.1

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

African (AFR) AF: 0.132 AC: 5485 AN: 41530

American (AMR) AF: 0.132 AC: 2024 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 819 AN: 3466

East Asian (EAS) AF: 0.169 AC: 874 AN: 5168

South Asian (SAS) AF: 0.190 AC: 918 AN: 4826

European-Finnish (FIN) AF: 0.0921 AC: 978 AN: 10614

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10691 AN: 68012

Other (OTH) AF: 0.169 AC: 357 AN: 2112

Alfa AF: 0.0756 Hom.: 99

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0010
DANN	Benign	0.51
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13248420; hg19: chr8-6337999;