rs200277422

chr8-60795083-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_017780.4(CHD7):c.2194C>G(p.Pro732Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,613,558 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). Synonymous variant affecting the same amino acid position (i.e. P732P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 6.35

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD7
• BP4: Computational evidence support a benign effect (MetaRNN=0.24783301).
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.2194C>G	p.Pro732Ala	missense_variant	4/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.2194C>G	p.Pro732Ala	missense_variant	4/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000682 AC: 17 AN: 249104 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000133

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 727010

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74288

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	This variant is associated with the following publications: (PMID: 16155193, 23526466, 22539353) -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2014	- -

CHARGE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2019

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	0.082
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	24
Dann	Benign	0.93
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	0.024
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.55	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.36	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.14	B;.
Vest4		0.35
MVP		0.91
MPC		0.14
ClinPred		0.12	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.28

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: rs200277422; hg19: chr8-61707642;