rs746837682

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS1

The NM_017780.4(CHD7):c.1672C>G(p.Pro558Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000239 in 1,549,408 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P558L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CHD7
NM_017780.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.51

Publications

3 publications found

Variant links:

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

CHD7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21068847).

BP6

Variant 8-60781006-C-G is Benign according to our data. Variant chr8-60781006-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 570104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000723 (11/152150) while in subpopulation AMR AF = 0.000524 (8/15274). AF 95% confidence interval is 0.00026. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4 link	c.1672C>G	p.Pro558Ala	missense_variant	Exon 3 of 38	ENST00000423902.7	NP_060250.2	Q9P2D1-1Q6ZWF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7 link	c.1672C>G	p.Pro558Ala	missense_variant	Exon 3 of 38	5	NM_017780.4	ENSP00000392028.1		Q9P2D1-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000643

AC:

AN:

202028

AF XY:

0.0000545

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.000218

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1397258

Hom.:

Cov.:

AF XY:

0.0000188

AC XY:

AN XY:

690704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30574

American (AMR)

AF:

0.000482

AC:

AN:

31100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22812

East Asian (EAS)

AF:

0.00

AC:

AN:

38900

South Asian (SAS)

AF:

0.00

AC:

AN:

74232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5468

European-Non Finnish (NFE)

AF:

0.00000829

AC:

AN:

1085600

Other (OTH)

AF:

0.0000348

AC:

AN:

57450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41414

American (AMR)

AF:

0.000524

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 12, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21158681) -

CHARGE syndrome

Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 13, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

0.97

L;L;L

PhyloP100

6.5

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.078

T;D;T

Sift4G

Benign

0.79

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.53

MutPred

0.15

Loss of glycosylation at P558 (P = 0.0426);Loss of glycosylation at P558 (P = 0.0426);Loss of glycosylation at P558 (P = 0.0426);

MVP

0.79

MPC

0.29

ClinPred

0.22

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.090

gMVP

0.37

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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rs746837682

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over