rs61978638

chr8-60801587-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_017780.4(CHD7):c.2436A>T(p.Lys812Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,571,574 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 2.04

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD7
• BP4: Computational evidence support a benign effect (MetaRNN=0.00971055).
• BP6: Variant 8-60801587-A-T is Benign according to our data. Variant chr8-60801587-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198223.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6, Benign=3}. Variant chr8-60801587-A-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.2436A>T	p.Lys812Asn	missense_variant	6/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.2436A>T	p.Lys812Asn	missense_variant	6/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000240 AC: 45 AN: 187124 Hom.: 0 AF XY: 0.000141 AC XY: 14 AN XY: 99622

Gnomad AFR exome AF: 0.00334

Gnomad AMR exome AF: 0.000217

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: 0.0000255

Gnomad OTH exome AF: 0.000201

GnomAD4 exome AF: 0.000101 AC: 144 AN: 1419268 Hom.: 0 Cov.: 29 AF XY: 0.0000769 AC XY: 54 AN XY: 702066

Gnomad4 AFR exome AF: 0.00295

Gnomad4 AMR exome AF: 0.000181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000248

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000551

Gnomad4 OTH exome AF: 0.000526

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74486

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000213 Hom.: 1

Bravo AF: 0.00104

ESP6500AA AF: 0.00274 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000201 AC: 24

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2017	Variant summary: The CHD7 c.2436A>T (p.Lys812Asn) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 15/29850 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.004964 (15/3022). This frequency is about 113 times the estimated maximal expected allele frequency of a pathogenic CHD7 variant (0.0000438), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in one CHARGE syndrome patient without strong evidence for causality (Janssen_HM_2012), and it has been classified as benign by multiple publications (Bergman_HM_2012, Janssen_HM_2012). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign and one lab classified it as uncertain significance. Taken together, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2018	The p.Lys812Asn variant in CHD7 is classified as likely benign because it has be en identified in 0.3% (59/19166) of African chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org). ACMG/AMP Criteria applie d: BS1. -

CHARGE association;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

CHD7 NM_017780 exon 6 p.Lys812Asn (c.2436A>T):This variant has not been reported in the literature but is present in 0.3% (59/19166) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61978638). This variant is present in ClinVar (Variation ID:198223). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2016

This 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. -

CHD7-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

CHARGE association Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.16
Sift	Benign	0.050	D;D
Sift4G	Benign	0.11	T;D
Polyphen		0.24	B;.
Vest4		0.30
MutPred		0.46		Loss of methylation at K812 (P = 7e-04);Loss of methylation at K812 (P = 7e-04);
MVP		0.59
MPC		0.52
ClinPred		0.050	T
GERP RS		5.0
Varity_R		0.47
gMVP		0.34

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: rs61978638; hg19: chr8-61714146;