8-6406391-A-T

Variant names:

• chr8-6406391-A-T
• rs2916656
• ENST00000500118.5:n.190T>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.190T>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 0.0935 in 512,142 control chromosomes in the GnomAD database, including 3,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1715 hom., cov: 34)
  • Exomes 𝑓: 0.080 (1431 hom.)
• Consequence: MCPH1-DT ENST00000500118.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.721
• Publications: 2 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=-0.82).
• BP6: Variant 8-6406391-A-T is Benign according to our data. Variant chr8-6406391-A-T is described in ClinVar as [Benign]. Clinvar id is 1243287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.-277A>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.-277A>T		upstream_gene_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19172 AN: 152070 Hom.: 1707 Cov.: 34

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0713

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0151

Gnomad SAS AF: 0.0640

Gnomad FIN AF: 0.0638

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.0839

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.0796 AC: 28663 AN: 359954 Hom.: 1431 Cov.: 0 AF XY: 0.0792 AC XY: 14917 AN XY: 188400

African (AFR) AF: 0.244 AC: 1838 AN: 7532

American (AMR) AF: 0.0598 AC: 669 AN: 11190

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 1636 AN: 11130

East Asian (EAS) AF: 0.00502 AC: 124 AN: 24698

South Asian (SAS) AF: 0.0611 AC: 1780 AN: 29142

European-Finnish (FIN) AF: 0.0568 AC: 1573 AN: 27718

Middle Eastern (MID) AF: 0.131 AC: 214 AN: 1628

European-Non Finnish (NFE) AF: 0.0831 AC: 18700 AN: 225138

Other (OTH) AF: 0.0978 AC: 2129 AN: 21778

GnomAD4 genome AF: 0.126 AC: 19199 AN: 152188 Hom.: 1715 Cov.: 34 AF XY: 0.122 AC XY: 9110 AN XY: 74424

African (AFR) AF: 0.252 AC: 10442 AN: 41502

American (AMR) AF: 0.0712 AC: 1089 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 495 AN: 3468

East Asian (EAS) AF: 0.0149 AC: 77 AN: 5166

South Asian (SAS) AF: 0.0647 AC: 312 AN: 4822

European-Finnish (FIN) AF: 0.0638 AC: 677 AN: 10618

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.0838 AC: 5701 AN: 67992

Other (OTH) AF: 0.105 AC: 221 AN: 2112

Alfa AF: 0.0366 Hom.: 32

Bravo AF: 0.133

Asia WGS AF: 0.0590 AC: 208 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

- -

Jul 08, 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	-0.82
CADD	Benign	2.3
DANN	Benign	0.70
PhyloP100		-0.72
PromoterAI		0.0052	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2916656; hg19: chr8-6263912;