rs886040995

Positions:

• chr8-60852682-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017780.4(CHD7):​c.6079C>T​(p.Arg2027*) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.16

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]

CHD7 (HGNC:):

ACMG classification

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 8-60852682-C-T is Pathogenic according to our data. Variant chr8-60852682-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 267435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60852682-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.6079C>T	p.Arg2027*	stop_gained	30/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.6079C>T	p.Arg2027*	stop_gained	30/38	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1717-9547C>T		intron_variant		1		ENSP00000437061.1
CHD7	ENST00000695853.1	n.6079C>T		non_coding_transcript_exon_variant	30/37			ENSP00000512218.1
CHD7	ENST00000527921.1	n.*43C>T		downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.6079C>T;p.(Arg2027*) variant creates a premature translational stop signal in the CHD7 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 267435; PMID: 16155193; 27061523; 29300383) - PS4. This variant is not present in population databases (rs886040995, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 16155193, 27061523, 29300383) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	research	Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School	Oct 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 16, 2020	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 22461308, 25077900). This variant has been reported de novo in individuals affected with CHARGE (PMID: 16155193, 22461308, 27061523). ClinVar contains an entry for this variant (Variation ID: 267435). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg2027*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Arg227Ter variant was identified by our study in one individual with CHARGE syndrome. The p.Arg227Ter variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Apr 26, 2018	A heterozygous nonsense variant, NM_017780.3(CHD7):c.6079C>T, has been identified in exon 30 of 38 in the CHD7 gene. The variant is predicted to result in a premature stop codon at position 2027 of the protein, NP_060250.2(CHD7):p.(Arg2027*). The variant is predicted to result in loss of protein function either through truncation (downstream functional domains would be affected) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, dbSNP, 1000G) and has been previously described as pathogenic in multiple individuals with CHARGE syndrome (ClinVar, Jongmans et al., (2016), Busa et al., (2016)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 05, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2020	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Approximately 45% of CHD7 pathogenic variants are nonsense changes (Janssen et al., 2012; Zentner et al, 2010); This variant is associated with the following publications: (PMID: 27061523, 29300383, 25525159, 16155193, 22461308, 21158681, 23333604, 32625235, 31827275) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.86
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886040995; hg19: chr8-61765241; COSMIC: COSV71109635; COSMIC: COSV71109635;