rs61995713

chr8-60742288-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017780.4(CHD7):c.856A>G(p.Arg286Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,613,932 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.40

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD7
• BP4: Computational evidence support a benign effect (MetaRNN=0.009042203).
• BP6: Variant 8-60742288-A-G is Benign according to our data. Variant chr8-60742288-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 158328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60742288-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00271 (412/152252) while in subpopulation AFR AF= 0.00944 (392/41540). AF 95% confidence interval is 0.00867. There are 1 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 411 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.856A>G	p.Arg286Gly	missense_variant	2/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.856A>G	p.Arg286Gly	missense_variant	2/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00944

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000667 AC: 166 AN: 249002 Hom.: 1 AF XY: 0.000437 AC XY: 59 AN XY: 135148

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.000261

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000291 AC: 426 AN: 1461680 Hom.: 2 Cov.: 33 AF XY: 0.000242 AC XY: 176 AN XY: 727128

Gnomad4 AFR exome AF: 0.0107

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00271 AC: 412 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74456

Gnomad4 AFR AF: 0.00944

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000518 Hom.: 1

Bravo AF: 0.00311

ESP6500AA AF: 0.00783 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000836 AC: 101

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 20, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Arg286Gly in exon 2 of CHD7: This variant is not expected to have clinical significance because it has been identified in 0.99% (95/9614) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61995713). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

CHARGE syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 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. -

CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2019

- -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.60	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.16	T;D;T
Polyphen		0.0	B;.;.
Vest4		0.75
MVP		1.0
MPC		0.18
ClinPred		0.0084	T
GERP RS		2.6
Varity_R		0.10
gMVP		0.48

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: rs61995713; hg19: chr8-61654847; COSMIC: COSV101418683; COSMIC: COSV101418683;