8-6406364-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000500118.5(MCPH1-DT):​n.217G>C 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 0.00449 in 494,966 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0048 (10 hom.)
• Consequence: MCPH1-DT ENST00000500118.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-6406364-C-G is Benign according to our data. Variant chr8-6406364-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1212188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1-DT	NR_040040.1	n.185G>C		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>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
MCPH1-DT	ENST00000523225.2	n.250G>C		non_coding_transcript_exon_variant	Exon 3 of 3	3
MCPH1-DT	ENST00000606853.3	n.235G>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 585 AN: 152178 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00645

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00477 AC: 1636 AN: 342670 Hom.: 10 Cov.: 0 AF XY: 0.00456 AC XY: 814 AN XY: 178558

African (AFR) AF: 0.00121 AC: 9 AN: 7430

American (AMR) AF: 0.000490 AC: 5 AN: 10200

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 20 AN: 10850

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

South Asian (SAS) AF: 0.00115 AC: 28 AN: 24434

European-Finnish (FIN) AF: 0.00852 AC: 230 AN: 27008

Middle Eastern (MID) AF: 0.00190 AC: 3 AN: 1578

European-Non Finnish (NFE) AF: 0.00585 AC: 1264 AN: 215892

Other (OTH) AF: 0.00366 AC: 77 AN: 21028

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152296 Hom.: 5 Cov.: 34 AF XY: 0.00381 AC XY: 284 AN XY: 74480

African (AFR) AF: 0.00101 AC: 42 AN: 41564

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00645 AC: 439 AN: 68022

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0112 Hom.: 4

Bravo AF: 0.00272

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 08, 2019

GeneDx

Significance: Likely 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	-0.80
CADD	Benign	4.5
DANN	Benign	0.60
PhyloP100		0.071
PromoterAI		-0.038	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;