8-60742036-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.604C>T(p.Gln202Ter) 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:3
• 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]

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 8-60742036-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	UniProt
CHD7	NM_017780.4	c.604C>T	p.Gln202Ter	stop_gained	2/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.604C>T	p.Gln202Ter	stop_gained	2/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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. -

CHD7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.87
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554581277; hg19: chr8-61654595; COSMIC: COSV101418413; COSMIC: COSV101418413;