rs1974946

Variant names:

• chr8-6631266-G-A
• rs1974946
• NM_024596.5:c.2452+9575G>A

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+9575G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,072 control chromosomes in the GnomAD database, including 4,967 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 0.25 (4967 hom., cov: 33)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.580
• 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-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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2452+9575G>A		intron_variant	Intron 13 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2452+9575G>A		intron_variant	Intron 13 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38272 AN: 151954 Hom.: 4968 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.0901

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.252 AC: 38298 AN: 152072 Hom.: 4967 Cov.: 33 AF XY: 0.249 AC XY: 18504 AN XY: 74328

African (AFR) AF: 0.253 AC: 10473 AN: 41464

American (AMR) AF: 0.187 AC: 2854 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 868 AN: 3470

East Asian (EAS) AF: 0.0903 AC: 469 AN: 5192

South Asian (SAS) AF: 0.233 AC: 1125 AN: 4826

European-Finnish (FIN) AF: 0.254 AC: 2675 AN: 10544

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19067 AN: 67966

Other (OTH) AF: 0.250 AC: 530 AN: 2116

Alfa AF: 0.268 Hom.: 701

Bravo AF: 0.245

Asia WGS AF: 0.165 AC: 574 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.2
DANN	Benign	0.78
PhyloP100		-0.58
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: rs1974946; hg19: chr8-6488787;