rs2442517

Variant names:

• chr8-6434003-A-G
• rs2442517
• NM_024596.5:c.322-2045A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-6434003-A-G
• chr8-6434003-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):​c.322-2045A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 151,868 control chromosomes in the GnomAD database, including 15,306 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (15306 hom., cov: 31)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.475
• Publications: 5 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: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.322-2045A>G		intron	N/A	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.322-2045A>G		intron	N/A	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.322-2045A>G		intron	N/A	NP_001397846.1	A0A8I5KPV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.322-2045A>G		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.322-2045A>G		intron	N/A	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.322-2045A>G		intron	N/A	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65126 AN: 151748 Hom.: 15304 Cov.: 31

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.463

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

GnomAD4 genome AF: 0.429 AC: 65140 AN: 151868 Hom.: 15306 Cov.: 31 AF XY: 0.441 AC XY: 32733 AN XY: 74212

African (AFR) AF: 0.234 AC: 9676 AN: 41398

American (AMR) AF: 0.529 AC: 8072 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1647 AN: 3470

East Asian (EAS) AF: 0.758 AC: 3907 AN: 5152

South Asian (SAS) AF: 0.621 AC: 2988 AN: 4808

European-Finnish (FIN) AF: 0.520 AC: 5465 AN: 10512

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31810 AN: 67964

Other (OTH) AF: 0.468 AC: 986 AN: 2108

Alfa AF: 0.458 Hom.: 49889

Bravo AF: 0.420

Asia WGS AF: 0.668 AC: 2319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.35
PhyloP100		-0.47
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: rs2442517; hg19: chr8-6291524;