8-60852186-C-T

Position:

• chr8-60852186-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.5833C>T​(p.Arg1945Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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:5
• Conservation: PhyloP100: 1.51

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 8-60852186-C-T is Pathogenic according to our data. Variant chr8-60852186-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 267434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60852186-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.5833C>T	p.Arg1945Ter	stop_gained	29/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.5833C>T	p.Arg1945Ter	stop_gained	29/38	5	NM_017780.4	ENSP00000392028	P1
CHD7	ENST00000524602.5	c.1717-10043C>T		intron_variant		1		ENSP00000437061
CHD7	ENST00000527921.1	n.324C>T		non_coding_transcript_exon_variant	4/5	4
CHD7	ENST00000695853.1	c.5833C>T	p.Arg1945Ter	stop_gained, NMD_transcript_variant	29/37			ENSP00000512218

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 21, 2021	This variant has been reported to be de novo in individuals affected with CHARGE syndrome and in other individuals affected with this disease (PMID: 16155193, 16400610, 21158681). ClinVar contains an entry for this variant (Variation ID: 267434). 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 is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg1945*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	This variant is predicted to introduce premature stop codon that may result in a truncated protein or transcript codon that may undergo nonsense-mediated mRNA decay. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2024	Apparently de novo variant in a patient with multiple congenital anomalies (PMID: 16155193); 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16400610, 32804436, 32754152, 16155193, 35015700, 32978145, 27321065) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CHD7: PVS1, PS2, PS4, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.87
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs757160222; hg19: chr8-61764745;