rs1554597716

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017780.4(CHD7):​c.3106C>T​(p.Arg1036*) 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

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.59
Variant links:
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 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 8-60822651-C-T is Pathogenic according to our data. Variant chr8-60822651-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 488373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CHD7NM_017780.4 linkc.3106C>T p.Arg1036* stop_gained 12/38 ENST00000423902.7 NP_060250.2 Q9P2D1-1Q6ZWF9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHD7ENST00000423902.7 linkc.3106C>T p.Arg1036* stop_gained 12/385 NM_017780.4 ENSP00000392028.1 Q9P2D1-1
CHD7ENST00000524602.5 linkc.1717-39578C>T intron_variant 1 ENSP00000437061.1 Q9P2D1-4
CHD7ENST00000525508.1 linkc.3106C>T p.Arg1036* stop_gained 11/125 ENSP00000436027.1 Q9P2D1-2
CHD7ENST00000695853.1 linkn.3106C>T non_coding_transcript_exon_variant 12/37 ENSP00000512218.1 A0A8Q3WKT9

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
LINK: link

Submissions by phenotype

CHARGE syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-In-silico prediction tools (MutationTaster and CADD phred) are consistent in predicting the variant to be damaging to CHD7 protein function. This variant is predicted to cause premature termination of the transcript, which will either lead to the nonsense-mediated mRNA decay or formation of a truncated protein product. This variant has also been reported in individuals affected with CHARGE syndrome (ClinVar ID-488373; Moccia et al., 2018). The clinical features in the proband overlap with CHARGE syndrome. -
Pathogenic, no assertion criteria providedresearchSbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical SchoolOct 27, 2017- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Translational Omics - GOSgene, University College LondonMar 16, 2018- -
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 08, 2022Nonsense 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16155193, 29300383, 33502061, 22462537, 21158681, 25525159, 16615981, 30498854, 23024289, 30049826, 34134972) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
42
DANN
Uncertain
1.0
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.92
D
Vest4
0.88
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554597716; hg19: chr8-61735210; COSMIC: COSV71115240; API