8-6406418-C-T

Variant names:

• chr8-6406418-C-T
• rs2243755
• ENST00000500118.5:n.163G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000749264.1(MCPH1-DT):​n.127+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 545,814 control chromosomes in the GnomAD database, including 130,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (30142 hom., cov: 33)
  • Exomes 𝑓: 0.71 (100728 hom.)
• Consequence: MCPH1-DT ENST00000749264.1 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.19
• Publications: 6 publications found

Genes affected

MCPH1-DT (HGNC:55599): (MCPH1 divergent transcript)

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-6406418-C-T is Benign according to our data. Variant chr8-6406418-C-T is described in ClinVar as [Benign]. Clinvar id is 1247321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.-250C>T		upstream_gene_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.-250C>T		upstream_gene_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90018 AN: 151754 Hom.: 30146 Cov.: 33

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.614

GnomAD4 exome AF: 0.707 AC: 278405 AN: 393944 Hom.: 100728 Cov.: 3 AF XY: 0.704 AC XY: 146051 AN XY: 207576

African (AFR) AF: 0.299 AC: 2394 AN: 8020

American (AMR) AF: 0.556 AC: 7447 AN: 13402

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 7880 AN: 11818

East Asian (EAS) AF: 0.488 AC: 12669 AN: 25976

South Asian (SAS) AF: 0.618 AC: 23158 AN: 37492

European-Finnish (FIN) AF: 0.800 AC: 23183 AN: 28974

Middle Eastern (MID) AF: 0.646 AC: 1126 AN: 1742

European-Non Finnish (NFE) AF: 0.760 AC: 184690 AN: 243136

Other (OTH) AF: 0.678 AC: 15858 AN: 23384

GnomAD4 genome AF: 0.593 AC: 90023 AN: 151870 Hom.: 30142 Cov.: 33 AF XY: 0.591 AC XY: 43899 AN XY: 74236

African (AFR) AF: 0.277 AC: 11487 AN: 41470

American (AMR) AF: 0.564 AC: 8614 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2319 AN: 3464

East Asian (EAS) AF: 0.465 AC: 2379 AN: 5114

South Asian (SAS) AF: 0.610 AC: 2942 AN: 4820

European-Finnish (FIN) AF: 0.779 AC: 8236 AN: 10568

Middle Eastern (MID) AF: 0.579 AC: 169 AN: 292

European-Non Finnish (NFE) AF: 0.765 AC: 51883 AN: 67854

Other (OTH) AF: 0.614 AC: 1297 AN: 2112

Alfa AF: 0.711 Hom.: 17057

Bravo AF: 0.563

Asia WGS AF: 0.551 AC: 1916 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.75
PhyloP100		-1.2
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2243755; hg19: chr8-6263939;