ENST00000500118.5:n.217G>A

Variant names:

• chr8-6406364-C-T
• rs576392182
• ENST00000500118.5:n.217G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000500118.5(MCPH1-DT):​n.217G>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 0.00000292 in 342,678 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MCPH1-DT ENST00000500118.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1-DT	NR_040040.1	n.185G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1-DT	ENST00000500118.5	n.217G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
MCPH1-DT	ENST00000523225.2	n.250G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3
MCPH1-DT	ENST00000606853.3	n.235G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000292 AC: 1 AN: 342678 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 178562

African (AFR) AF: 0.000135 AC: 1 AN: 7430

American (AMR) AF: 0.00 AC: 0 AN: 10200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10850

East Asian (EAS) AF: 0.00 AC: 0 AN: 24250

South Asian (SAS) AF: 0.00 AC: 0 AN: 24434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 215900

Other (OTH) AF: 0.00 AC: 0 AN: 21028

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.74
PhyloP100		0.071
PromoterAI		0.0085	Neutral

Splicing

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

Other links and lift over

dbSNP: rs576392182; hg19: chr8-6263885;