8-60742036-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017780.4(CHD7):c.604C>T(p.Gln202*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CHD7
NM_017780.4 stop_gained
NM_017780.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.81
Genes affected
CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-60742036-C-T is Pathogenic according to our data. Variant chr8-60742036-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 459557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60742036-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHD7 | NM_017780.4 | c.604C>T | p.Gln202* | stop_gained | 2/38 | ENST00000423902.7 | NP_060250.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.604C>T | p.Gln202* | stop_gained | 2/38 | 5 | NM_017780.4 | ENSP00000392028.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
CHARGE syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 03, 2018 | A heterozygous nonsense variant, NM_017780.3(CHD7):c.604C>T, has been identified in exon 2 of 38 of the CHD7 gene. This variant is predicted to result in a premature stop codon at position 202 of the protein, NP_060250.2(CHD7):p.(Gln202*), and predicted to result in loss of protein function either through truncation (including loss of several conserved domains) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. This variant is absent in population databases (gnomAD, dbSNP, 1000G) and has been previously described as pathogenic in two individuals with CHARGE syndrome (CHD7 database). Analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 10, 2017 | This sequence change creates a premature translational stop signal at codon 202 (p.Gln202*) of the CHD7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 16400610, 22461308). This particular variant has been reported in the literature arising de novo in an individual affected with CHARGE syndrome (PMID: 22461308). For these reasons, this variant has been classified as Pathogenic. - |
CHD7-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 30, 2023 | The CHD7 c.604C>T variant is predicted to result in premature protein termination (p.Gln202*). This variant has been reported in multiple individuals with CHARGE syndrome (Janssen et al 2012. PubMed ID: 22461308; eTable 3 in Lunke et al. 2020. PubMed ID: 32573669; Supplementary Table 1 in Levy et al. 2022. PubMed ID: 35904121) with the variant having occurred de novo in at least one affected individual (Janssen et al. 2012. PubMed ID: 22461308). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CHD7 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at