rs1554604771

Variant names:

• chr8-60856027-GC-CT
• rs1554604771
• NM_017780.4:c.6989_6990delGCinsCT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_017780.4(CHD7):​c.6989_6990delGCinsCT​(p.Gly2330Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000221 in 61 alleles, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G2330G) has been classified as Benign.

• Frequency: GnomAD MNV: 𝑓 0.00022 Genomes: not found (cov: 33)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

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]

CHD7 Gene-Disease associations (from GenCC):

• CHARGE syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Broad Center for Mendelian Genomics, ClinGen, G2P
• hypogonadotropic hypogonadism 5 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 8-60856027-GC-CT is Benign according to our data. Variant chr8-60856027-GC-CT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529148.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.6989_6990delGCinsCT	p.Gly2330Ala	missense_variant		ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.6989_6990delGCinsCT	p.Gly2330Ala	missense_variant		5	NM_017780.4	ENSP00000392028.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

GnomAD MNV AF: 0.000221 AC: 61 Hom.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 24, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6989_6990delGCinsCT variant (also known as p.G2330A), located in coding exon 32 of the CHD7 gene, results from an in-frame deletion of GC and insertion of CT at nucleotide positions 6989 to 6990. This results in the substitution of the glycine residue for an alanine residue at codon 2330, an amino acid with similar properties. In one study, c.6989G>C (p.G2330A) was reported as a rare missense variation of unknown pathogenicity identified in a cohort of samples submitted for CHD7 analysis (Bartels CF et al. Genet Test Mol Biomarkers, 2010 Dec;14:881-91). In another study, c.6989G>C (p.G2330A) was classified as a benign CHD7 missense variant present in two or more controls and/or found in the homozygous state; however, more specific information was not provided (Bergman JE et al. Hum. Mutat., 2012 Aug;33:1251-60). This amino acid position is highly conserved in available vertebrate species. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Jul 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6989_6990delinsCT variant in CHD7 is classified as benign because it had b een identified in 0.26% (61/23434) of African chromosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs77704609 and rs559382275). ACMG/AMP Criteria applied: BA1. -

CHARGE syndrome Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554604771; hg19: chr8-61768586;