rs11774231

Positions:

• chr8-6646795-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):​c.*3746C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0633 in 152,202 control chromosomes in the GnomAD database, including 381 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 0.063 (381 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: MCPH1 NM_024596.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.975

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCPH1	NM_024596.5	c.*3746C>T		3_prime_UTR_variant	14/14	ENST00000344683.10
MCPH1-AS1	NR_125386.1	n.70-19485G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCPH1	ENST00000344683.10	c.*3746C>T		3_prime_UTR_variant	14/14	1	NM_024596.5	P1
MCPH1-AS1	ENST00000661193.1	n.70-11376G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9628 AN: 152084 Hom.: 382 Cov.: 33

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0971

Gnomad FIN AF: 0.0427

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0861

Gnomad OTH AF: 0.0774

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0633 AC: 9632 AN: 152202 Hom.: 381 Cov.: 33 AF XY: 0.0616 AC XY: 4587 AN XY: 74422

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.0537

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0982

Gnomad4 FIN AF: 0.0427

Gnomad4 NFE AF: 0.0861

Gnomad4 OTH AF: 0.0766

Alfa AF: 0.0793 Hom.: 197

Bravo AF: 0.0627

Asia WGS AF: 0.0460 AC: 159 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs11774231; hg19: chr8-6504316;