rs2442546

Variant names:

• chr8-6414635-G-A
• rs2442546
• NM_024596.5:c.115-130G>A

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.115-130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 906,062 control chromosomes in the GnomAD database, including 263,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.65 (35945 hom., cov: 33)
  • Exomes 𝑓: 0.77 (227583 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.458
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-6414635-G-A is Benign according to our data. Variant chr8-6414635-G-A is described in ClinVar as Benign. ClinVar VariationId is 673332.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.782 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.115-130G>A		intron	N/A	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.115-130G>A		intron	N/A	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.115-130G>A		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.115-130G>A		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.115-130G>A		intron	N/A	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.115-130G>A		intron	N/A	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98902 AN: 152054 Hom.: 35938 Cov.: 33

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.668

GnomAD4 exome AF: 0.772 AC: 581627 AN: 753890 Hom.: 227583 AF XY: 0.771 AC XY: 299476 AN XY: 388580

African (AFR) AF: 0.283 AC: 5188 AN: 18308

American (AMR) AF: 0.824 AC: 22075 AN: 26786

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 11768 AN: 17360

East Asian (EAS) AF: 0.762 AC: 23576 AN: 30948

South Asian (SAS) AF: 0.731 AC: 42633 AN: 58344

European-Finnish (FIN) AF: 0.876 AC: 28142 AN: 32138

Middle Eastern (MID) AF: 0.667 AC: 1723 AN: 2582

European-Non Finnish (NFE) AF: 0.790 AC: 420646 AN: 532380

Other (OTH) AF: 0.738 AC: 25876 AN: 35044

GnomAD4 genome AF: 0.650 AC: 98924 AN: 152172 Hom.: 35945 Cov.: 33 AF XY: 0.658 AC XY: 48996 AN XY: 74420

African (AFR) AF: 0.295 AC: 12242 AN: 41488

American (AMR) AF: 0.769 AC: 11743 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2379 AN: 3472

East Asian (EAS) AF: 0.748 AC: 3876 AN: 5184

South Asian (SAS) AF: 0.722 AC: 3486 AN: 4828

European-Finnish (FIN) AF: 0.877 AC: 9299 AN: 10600

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.788 AC: 53570 AN: 68002

Other (OTH) AF: 0.670 AC: 1416 AN: 2114

Alfa AF: 0.749 Hom.: 24260

Bravo AF: 0.628

Asia WGS AF: 0.712 AC: 2473 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.81
PhyloP100		0.46
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: rs2442546; hg19: chr8-6272156;