rs554647169

chr8-60742126-C-Achr8-60742126-C-T

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.694C>A(p.Pro232Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,613,972 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (7 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.54

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=0.008243531).
• BP6: Variant 8-60742126-C-A is Benign according to our data. Variant chr8-60742126-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 210725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60742126-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000407 (62/152272) while in subpopulation SAS AF= 0.0122 (59/4828). AF 95% confidence interval is 0.00973. There are 1 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.694C>A	p.Pro232Thr	missense_variant	2/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.694C>A	p.Pro232Thr	missense_variant	2/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152154 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00148 AC: 370 AN: 249276 Hom.: 1 AF XY: 0.00189 AC XY: 255 AN XY: 135240

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.000756 AC: 1105 AN: 1461700 Hom.: 7 Cov.: 32 AF XY: 0.00107 AC XY: 775 AN XY: 727134

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000663 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.00160 AC: 194

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2019	Variant summary: The variant, CHD7 c.694C>A (p.Pro232Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 246218 control chromosomes, predominantly at a frequency of 0.012 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9600 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHD7 causing Congenital Heart Disease phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.694C>A has been reported in the literature in an individual affected with Tetralogy of Fallot (DAlessandro_2016). However, this report does not provide unequivocal conclusions about association of the variant with Congenital Heart Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (X2) /likely benign (X2). Based on the evidence outlined above, the variant was classified as likely benign. -

CHARGE syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 05, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CHD7: BP4, BS1 -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 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. -

CHD7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 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). -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

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	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D;D;D
MetaRNN	Benign	0.0082	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.034
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.31	T;D;T
Polyphen		0.0030	B;.;.
Vest4		0.41
MutPred		0.26		Gain of catalytic residue at P232 (P = 0.0032);Gain of catalytic residue at P232 (P = 0.0032);Gain of catalytic residue at P232 (P = 0.0032);
MVP		0.73
MPC		0.36
ClinPred		0.019	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.44

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: rs554647169; hg19: chr8-61654685; COSMIC: COSV71112456; COSMIC: COSV71112456;