8-60852177-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_017780.4(CHD7):c.5824C>T(p.Arg1942Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017780.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.5824C>T | p.Arg1942Trp | missense_variant | Exon 29 of 38 | 5 | NM_017780.4 | ENSP00000392028.1 | ||
CHD7 | ENST00000524602.5 | c.1717-10052C>T | intron_variant | Intron 2 of 4 | 1 | ENSP00000437061.1 | ||||
CHD7 | ENST00000527921.1 | n.315C>T | non_coding_transcript_exon_variant | Exon 4 of 5 | 4 | |||||
CHD7 | ENST00000695853.1 | n.5824C>T | non_coding_transcript_exon_variant | Exon 29 of 37 | ENSP00000512218.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000323 AC: 8AN: 248056Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134936
GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461568Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40AN XY: 727076
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:2
CHD7: PP3 -
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CHARGE syndrome Uncertain:1Benign:1
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Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan, exon 29. (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition. Overall frequency: 0.003%, 8 Het, 0 Hom (subpopulation Ashkenazi Jewish: 0.02%, 2 Het). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD: p.(Arg1942Gln) (0.0008%, 1 het). Note: other changes also seen in the surrounding arginine residues, a string of five arginine residues . (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Only 1/4 in silico analyses damaging, glycine observed in sheep no changes in mammals and major amino acid change. (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region) (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant is absent in the population / or present in the population at <0.001 and has previously been described as variant of uncertain significance in multiple independent cases with consistent phenotype. ClinVar: 3x submitted as a VUS (1x Neurodevelopmental disorder, 1x CHARGE, 1x Not provided). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Inborn genetic diseases Uncertain:1
The p.R1942W variant (also known as c.5824C>T), located in coding exon 28 of the CHD7 gene, results from a C to T substitution at nucleotide position 5824. The arginine at codon 1942 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this variant remains unclear. -
Amenorrhea Uncertain:1
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CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at