ENST00000500118.5:n.29C>A

Variant names:

• chr8-6406552-G-T
• rs2916655
• ENST00000500118.5:n.29C>A

Variant summary

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

The ENST00000500118.5(MCPH1-DT):​n.29C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,140,492 control chromosomes in the GnomAD database, including 1,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (736 hom., cov: 34)
  • Exomes 𝑓: 0.017 (531 hom.)
• Consequence: MCPH1-DT ENST00000500118.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.285
• Publications: 3 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=-0.76).
• BP6: Variant 8-6406552-G-T is Benign according to our data. Variant chr8-6406552-G-T is described in ClinVar as [Benign]. Clinvar id is 1247952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.-116G>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.-116G>T		upstream_gene_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.0644 AC: 9797 AN: 152124 Hom.: 732 Cov.: 34

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0649

GnomAD4 exome AF: 0.0175 AC: 17276 AN: 988250 Hom.: 531 Cov.: 12 AF XY: 0.0168 AC XY: 8338 AN XY: 497382

African (AFR) AF: 0.186 AC: 3882 AN: 20910

American (AMR) AF: 0.0247 AC: 570 AN: 23118

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 309 AN: 17704

East Asian (EAS) AF: 0.00 AC: 0 AN: 32384

South Asian (SAS) AF: 0.0105 AC: 636 AN: 60626

European-Finnish (FIN) AF: 0.0272 AC: 1053 AN: 38676

Middle Eastern (MID) AF: 0.0513 AC: 175 AN: 3410

European-Non Finnish (NFE) AF: 0.0127 AC: 9512 AN: 747728

Other (OTH) AF: 0.0261 AC: 1139 AN: 43694

GnomAD4 genome AF: 0.0645 AC: 9823 AN: 152242 Hom.: 736 Cov.: 34 AF XY: 0.0644 AC XY: 4793 AN XY: 74428

African (AFR) AF: 0.185 AC: 7663 AN: 41516

American (AMR) AF: 0.0379 AC: 581 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4830

European-Finnish (FIN) AF: 0.0312 AC: 331 AN: 10624

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.0145 AC: 983 AN: 68014

Other (OTH) AF: 0.0643 AC: 136 AN: 2116

Alfa AF: 0.0296 Hom.: 64

Bravo AF: 0.0697

Asia WGS AF: 0.0170 AC: 61 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.1
DANN	Benign	0.52
PhyloP100		0.28
PromoterAI		0.28	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2916655; hg19: chr8-6264073;