rs61729627
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_017780.4(CHD7):c.6738G>A(p.Glu2246=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,517,488 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.014 ( 55 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 53 hom. )
Consequence
CHD7
NM_017780.4 synonymous
NM_017780.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0460
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 8-60853463-G-A is Benign according to our data. Variant chr8-60853463-G-A is described in ClinVar as [Benign]. Clinvar id is 95808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60853463-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.046 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2184/152308) while in subpopulation AFR AF= 0.0493 (2047/41560). AF 95% confidence interval is 0.0475. There are 55 homozygotes in gnomad4. There are 1071 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 2184 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD7 | NM_017780.4 | c.6738G>A | p.Glu2246= | synonymous_variant | 31/38 | ENST00000423902.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.6738G>A | p.Glu2246= | synonymous_variant | 31/38 | 5 | NM_017780.4 | P1 | |
CHD7 | ENST00000524602.5 | c.1717-8766G>A | intron_variant | 1 | |||||
CHD7 | ENST00000695853.1 | c.6738G>A | p.Glu2246= | synonymous_variant, NMD_transcript_variant | 31/37 |
Frequencies
GnomAD3 genomes ? AF: 0.0143 AC: 2172AN: 152190Hom.: 54 Cov.: 32
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GnomAD3 exomes AF: 0.00482 AC: 843AN: 175030Hom.: 17 AF XY: 0.00372 AC XY: 344AN XY: 92492
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GnomAD4 exome AF: 0.00160 AC: 2189AN: 1365180Hom.: 53 Cov.: 32 AF XY: 0.00143 AC XY: 958AN XY: 668520
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GnomAD4 genome ? AF: 0.0143 AC: 2184AN: 152308Hom.: 55 Cov.: 32 AF XY: 0.0144 AC XY: 1071AN XY: 74484
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ClinVar
Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:6
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 26, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 03, 2018 | Variant summary: CHD7 c.6738G>A results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0062 in 203528 control chromosomes, predominantly at a frequency of 0.049 within the African subpopulation in the gnomAD database, including 27 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is much greater than the estimated maximal expected allele frequency for a pathogenic variant in CHD7 causing Congenital Heart Disease phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 14, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 19, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
CHARGE syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 08, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at