8-60742851-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_017780.4(CHD7):ā€‹c.1419G>Cā€‹(p.Gly473Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,612,716 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0015 ( 2 hom., cov: 32)
Exomes š‘“: 0.0011 ( 13 hom. )

Consequence

CHD7
NM_017780.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.81
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
BP6
Variant 8-60742851-G-C is Benign according to our data. Variant chr8-60742851-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 95774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60742851-G-C is described in Lovd as [Likely_benign]. Variant chr8-60742851-G-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=1.81 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00112 (1632/1460370) while in subpopulation MID AF= 0.00537 (31/5768). AF 95% confidence interval is 0.00389. There are 13 homozygotes in gnomad4_exome. There are 840 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 221 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CHD7NM_017780.4 linkuse as main transcriptc.1419G>C p.Gly473Gly synonymous_variant 2/38 ENST00000423902.7 NP_060250.2 Q9P2D1-1Q6ZWF9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHD7ENST00000423902.7 linkuse as main transcriptc.1419G>C p.Gly473Gly synonymous_variant 2/385 NM_017780.4 ENSP00000392028.1 Q9P2D1-1

Frequencies

GnomAD3 genomes
AF:
0.00145
AC:
221
AN:
152228
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00222
Gnomad ASJ
AF:
0.0288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.000720
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00195
AC:
479
AN:
245896
Hom.:
5
AF XY:
0.00197
AC XY:
263
AN XY:
133334
show subpopulations
Gnomad AFR exome
AF:
0.000330
Gnomad AMR exome
AF:
0.00117
Gnomad ASJ exome
AF:
0.0290
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000628
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000810
Gnomad OTH exome
AF:
0.00586
GnomAD4 exome
AF:
0.00112
AC:
1632
AN:
1460370
Hom.:
13
Cov.:
32
AF XY:
0.00116
AC XY:
840
AN XY:
726290
show subpopulations
Gnomad4 AFR exome
AF:
0.000897
Gnomad4 AMR exome
AF:
0.00128
Gnomad4 ASJ exome
AF:
0.0297
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000779
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000436
Gnomad4 OTH exome
AF:
0.00307
GnomAD4 genome
AF:
0.00145
AC:
221
AN:
152346
Hom.:
2
Cov.:
32
AF XY:
0.00149
AC XY:
111
AN XY:
74512
show subpopulations
Gnomad4 AFR
AF:
0.000577
Gnomad4 AMR
AF:
0.00222
Gnomad4 ASJ
AF:
0.0288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000720
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00369
Hom.:
3
Bravo
AF:
0.00161
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 23, 2017p.Gly473Gly in exon 2 of CHD7: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.28% (174/62782) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs186394299). -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 08, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 07, 2016- -
not provided Benign:4
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024CHD7: BP4, BP7, BS1 -
CHARGE syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 11, 2016This alteration is classified as likely 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. -
CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 13, 2021- -
Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.59
CADD
Benign
8.1
DANN
Benign
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs186394299; hg19: chr8-61655410; API