8-60821922-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_017780.4(CHD7):c.2830C>T(p.Arg944Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,612,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R944H) has been classified as Likely benign.
Frequency
Consequence
NM_017780.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.2830C>T | p.Arg944Cys | missense_variant | Exon 10 of 38 | 5 | NM_017780.4 | ENSP00000392028.1 | ||
CHD7 | ENST00000524602.5 | c.1717-40307C>T | intron_variant | Intron 2 of 4 | 1 | ENSP00000437061.1 | ||||
CHD7 | ENST00000525508.1 | c.2830C>T | p.Arg944Cys | missense_variant | Exon 9 of 12 | 5 | ENSP00000436027.1 | |||
CHD7 | ENST00000695853.1 | n.2830C>T | non_coding_transcript_exon_variant | Exon 10 of 37 | ENSP00000512218.1 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151858Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000282 AC: 7AN: 247844Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134418
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1460960Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33AN XY: 726686
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151858Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74148
ClinVar
Submissions by phenotype
not provided Uncertain:2
Identified in a patient with hypogonadotropic hypogonadism (Zhang et al., 2019) and in a patient with constitutional delay of growth and puberty (Barroso et al., 2019) in published literature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24755471, 32851286, 31726455, 32134193) -
Variant summary: The CHD7 c.2830C>T (p.Arg944Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). Arg944 is located in the chromo domain, the P-loop containing nucleoside triphosphate hydrolase domain, and the SNF2-related N-terminal domain of the protein. This variant was found in 3/105356 control chromosomes at a frequency of 0.0000285, which is approximately 23 times the estimated maximal expected allele frequency of a pathogenic CHD7 variant (0.0000013), suggesting this variant may be a benign polymorphism. Taken together, this variant is classified as a VUS-possibly benign until additional information is available. -
CHARGE syndrome Benign:1
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CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at