rs61742801

Positions:

• chr8-60856870-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_017780.4(CHD7):​c.7590A>G​(p.Lys2530=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000767 in 1,554,658 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0044 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: CHD7 NM_017780.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.71

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-60856870-A-G is Benign according to our data. Variant chr8-60856870-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158318.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}. Variant chr8-60856870-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00438 (667/152302) while in subpopulation AFR AF= 0.0155 (646/41548). AF 95% confidence interval is 0.0146. There are 5 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 667 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.7590A>G	p.Lys2530=	synonymous_variant	34/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.7590A>G	p.Lys2530=	synonymous_variant	34/38	5	NM_017780.4	ENSP00000392028	P1

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152184 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00122 AC: 245 AN: 200010 Hom.: 1 AF XY: 0.000841 AC XY: 90 AN XY: 106978

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000418

Gnomad OTH exome AF: 0.000650

GnomAD4 exome AF: 0.000375 AC: 526 AN: 1402356 Hom.: 4 Cov.: 32 AF XY: 0.000328 AC XY: 227 AN XY: 691664

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.000569

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000249

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152302 Hom.: 5 Cov.: 33 AF XY: 0.00397 AC XY: 296 AN XY: 74490

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.00481

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Lys2530Lys in exon 34 of CHD7: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 1.54% (143/9280) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61742801). -
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	GeneDx	Apr 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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	Feb 27, 2024	Variant summary: CHD7 c.7590A>G alters a conserved nucleotide resulting in a synonymous change. Consensus agreement among computation 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 0.0012 in 200010 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 300 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHD7 causing CHARGE Syndrome phenotype (4.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. ClinVar contains an entry for this variant (Variation ID: 158318). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

CHARGE syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.6
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs61742801; hg19: chr8-61769429;