8-6406432-G-C

Variant names:

• chr8-6406432-G-C
• rs3020244
• ENST00000500118.5:n.149C>G

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.149C>G 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 0.125 in 557,098 control chromosomes in the GnomAD database, including 5,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3038 hom., cov: 34)
  • Exomes 𝑓: 0.11 (2951 hom.)
• Consequence: MCPH1-DT ENST00000500118.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.32
• 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=-0.74).
• BP6: Variant 8-6406432-G-C is Benign according to our data. Variant chr8-6406432-G-C is described in ClinVar as [Benign]. Clinvar id is 1238897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.-236G>C		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.-236G>C		upstream_gene_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25669 AN: 152090 Hom.: 3025 Cov.: 34

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.0771

Gnomad FIN AF: 0.0996

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.152

GnomAD4 exome AF: 0.108 AC: 43735 AN: 404890 Hom.: 2951 Cov.: 3 AF XY: 0.107 AC XY: 22888 AN XY: 213542

African (AFR) AF: 0.328 AC: 2698 AN: 8228

American (AMR) AF: 0.0845 AC: 1206 AN: 14274

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 2090 AN: 12096

East Asian (EAS) AF: 0.00550 AC: 146 AN: 26548

South Asian (SAS) AF: 0.0832 AC: 3310 AN: 39764

European-Finnish (FIN) AF: 0.0887 AC: 2597 AN: 29274

Middle Eastern (MID) AF: 0.194 AC: 346 AN: 1784

European-Non Finnish (NFE) AF: 0.113 AC: 28231 AN: 249040

Other (OTH) AF: 0.130 AC: 3111 AN: 23882

GnomAD4 genome AF: 0.169 AC: 25715 AN: 152208 Hom.: 3038 Cov.: 34 AF XY: 0.165 AC XY: 12255 AN XY: 74444

African (AFR) AF: 0.335 AC: 13887 AN: 41514

American (AMR) AF: 0.102 AC: 1561 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 568 AN: 3472

East Asian (EAS) AF: 0.0155 AC: 80 AN: 5172

South Asian (SAS) AF: 0.0777 AC: 375 AN: 4824

European-Finnish (FIN) AF: 0.0996 AC: 1057 AN: 10616

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.112 AC: 7617 AN: 67992

Other (OTH) AF: 0.151 AC: 319 AN: 2114

Alfa AF: 0.146 Hom.: 267

Bravo AF: 0.178

Asia WGS AF: 0.0740 AC: 261 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	-0.74
CADD	Benign	4.2
DANN	Benign	0.61
PhyloP100		1.3
PromoterAI		0.022	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: rs3020244; hg19: chr8-6263953;