8-6406426-C-G

Variant names:

• chr8-6406426-C-G
• rs2243756
• ENST00000500118.5:n.155G>C

Variant summary

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

The ENST00000749264.1(MCPH1-DT):​n.125G>C variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 549,296 control chromosomes in the GnomAD database, including 131,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (30102 hom., cov: 33)
  • Exomes 𝑓: 0.71 (101306 hom.)
• Consequence: MCPH1-DT ENST00000749264.1 splice_region, non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.969
• Publications: 4 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=-0.75).
• BP6: Variant 8-6406426-C-G is Benign according to our data. Variant chr8-6406426-C-G is described in ClinVar as [Benign]. Clinvar id is 1245106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.-242C>G		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.-242C>G		upstream_gene_variant		1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89833 AN: 151720 Hom.: 30106 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.613

GnomAD4 exome AF: 0.706 AC: 280423 AN: 397460 Hom.: 101306 Cov.: 3 AF XY: 0.702 AC XY: 147153 AN XY: 209520

African (AFR) AF: 0.292 AC: 2369 AN: 8102

American (AMR) AF: 0.552 AC: 7558 AN: 13686

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 7923 AN: 11898

East Asian (EAS) AF: 0.493 AC: 12905 AN: 26162

South Asian (SAS) AF: 0.615 AC: 23562 AN: 38336

European-Finnish (FIN) AF: 0.800 AC: 23257 AN: 29076

Middle Eastern (MID) AF: 0.641 AC: 1130 AN: 1762

European-Non Finnish (NFE) AF: 0.759 AC: 185791 AN: 244910

Other (OTH) AF: 0.677 AC: 15928 AN: 23528

GnomAD4 genome AF: 0.592 AC: 89837 AN: 151836 Hom.: 30102 Cov.: 33 AF XY: 0.590 AC XY: 43795 AN XY: 74214

African (AFR) AF: 0.273 AC: 11305 AN: 41466

American (AMR) AF: 0.564 AC: 8605 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2317 AN: 3462

East Asian (EAS) AF: 0.473 AC: 2417 AN: 5110

South Asian (SAS) AF: 0.611 AC: 2943 AN: 4820

European-Finnish (FIN) AF: 0.779 AC: 8228 AN: 10558

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51860 AN: 67838

Other (OTH) AF: 0.614 AC: 1296 AN: 2112

Alfa AF: 0.668 Hom.: 4541

Bravo AF: 0.562

Asia WGS AF: 0.553 AC: 1922 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

- -

Jun 16, 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	-0.75
CADD	Benign	2.7
DANN	Benign	0.46
PhyloP100		0.97
PromoterAI		-0.0053	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: rs2243756; hg19: chr8-6263947;