8-6631189-C-T

Variant names:

• chr8-6631189-C-T
• rs2912064
• NM_024596.5:c.2452+9498C>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.2452+9498C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 152,076 control chromosomes in the GnomAD database, including 11,102 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 0.38 (11102 hom., cov: 33)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.644
• 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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 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.2452+9498C>T		intron	N/A	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2594+6152C>T		intron	N/A	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001363979.1		c.2453-6712C>T		intron	N/A	NP_001350908.1	A0A8I5KW78

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2452+9498C>T		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000689348.1		c.2594+6152C>T		intron	N/A	ENSP00000509554.1	A0A8I5KV10
	MCPH1	ENST00000690826.1		c.2453-6712C>T		intron	N/A	ENSP00000510536.1	A0A8I5KW78

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57972 AN: 151958 Hom.: 11088 Cov.: 33

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.382 AC: 58039 AN: 152076 Hom.: 11102 Cov.: 33 AF XY: 0.385 AC XY: 28655 AN XY: 74358

African (AFR) AF: 0.423 AC: 17542 AN: 41496

American (AMR) AF: 0.384 AC: 5873 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1143 AN: 3464

East Asian (EAS) AF: 0.475 AC: 2454 AN: 5164

South Asian (SAS) AF: 0.408 AC: 1964 AN: 4818

European-Finnish (FIN) AF: 0.380 AC: 4015 AN: 10562

Middle Eastern (MID) AF: 0.339 AC: 99 AN: 292

European-Non Finnish (NFE) AF: 0.353 AC: 23974 AN: 67966

Other (OTH) AF: 0.364 AC: 770 AN: 2114

Alfa AF: 0.321 Hom.: 1904

Bravo AF: 0.381

Asia WGS AF: 0.410 AC: 1423 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.59
DANN	Benign	0.49
PhyloP100		-0.64
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: rs2912064; hg19: chr8-6488710;