8-6445888-T-G

Variant names:

• chr8-6445888-T-G
• rs2916750
• ENST00000519480.6:c.*333T>G

Variant summary

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

The ENST00000519480.6(MCPH1):​c.*333T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,038,434 control chromosomes in the GnomAD database, including 21,939 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 0.26 (7019 hom., cov: 33)
  • Exomes 𝑓: 0.18 (14920 hom.)
• Consequence: MCPH1 ENST00000519480.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.317
• 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: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1825+341T>G		intron_variant	Intron 8 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.1825+341T>G		intron_variant	Intron 8 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40159 AN: 152012 Hom.: 7003 Cov.: 33

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.176 AC: 156223 AN: 886304 Hom.: 14920 Cov.: 25 AF XY: 0.176 AC XY: 72482 AN XY: 411974

African (AFR) AF: 0.518 AC: 8886 AN: 17154

American (AMR) AF: 0.141 AC: 680 AN: 4828

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 2119 AN: 6744

East Asian (EAS) AF: 0.173 AC: 1289 AN: 7470

South Asian (SAS) AF: 0.229 AC: 4516 AN: 19762

European-Finnish (FIN) AF: 0.0873 AC: 185 AN: 2120

Middle Eastern (MID) AF: 0.289 AC: 534 AN: 1850

European-Non Finnish (NFE) AF: 0.166 AC: 131967 AN: 796012

Other (OTH) AF: 0.199 AC: 6047 AN: 30364

GnomAD4 genome AF: 0.264 AC: 40212 AN: 152130 Hom.: 7019 Cov.: 33 AF XY: 0.257 AC XY: 19136 AN XY: 74404

African (AFR) AF: 0.499 AC: 20690 AN: 41436

American (AMR) AF: 0.185 AC: 2825 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1021 AN: 3472

East Asian (EAS) AF: 0.182 AC: 941 AN: 5176

South Asian (SAS) AF: 0.245 AC: 1185 AN: 4830

European-Finnish (FIN) AF: 0.107 AC: 1133 AN: 10610

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11670 AN: 68000

Other (OTH) AF: 0.264 AC: 557 AN: 2110

Alfa AF: 0.195 Hom.: 4514

Bravo AF: 0.279

Asia WGS AF: 0.224 AC: 781 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.63
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2916750; hg19: chr8-6303409;