8-60853012-A-G
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_017780.4(CHD7):āc.6287A>Gā(p.His2096Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2096Y) has been classified as Likely benign.
Frequency
Consequence
NM_017780.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD7 | NM_017780.4 | c.6287A>G | p.His2096Arg | missense_variant | 31/38 | ENST00000423902.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.6287A>G | p.His2096Arg | missense_variant | 31/38 | 5 | NM_017780.4 | P1 | |
CHD7 | ENST00000524602.5 | c.1717-9217A>G | intron_variant | 1 | |||||
CHD7 | ENST00000695853.1 | c.6287A>G | p.His2096Arg | missense_variant, NMD_transcript_variant | 31/37 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461712Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727138
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
CHARGE syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | This missense change has been observed in individual(s) with CHARGE syndrome (PMID: 16400610). In at least one individual the variant was observed to be de novo. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2096 of the CHD7 protein (p.His2096Arg). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 158309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHD7 protein function. Experimental studies have shown that this missense change affects CHD7 function (PMID: 20453063). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 05, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at