rs200898742

chr8-60742144-G-Achr8-60742144-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_017780.4(CHD7):c.712G>A(p.Val238Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,613,892 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V238L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.42

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD7
• BP4: Computational evidence support a benign effect (MetaRNN=0.0068236887).
• BP6: Variant 8-60742144-G-A is Benign according to our data. Variant chr8-60742144-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195326.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00144 (219/152204) while in subpopulation AFR AF= 0.00511 (212/41518). AF 95% confidence interval is 0.00454. There are 1 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.712G>A	p.Val238Met	missense_variant	2/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.712G>A	p.Val238Met	missense_variant	2/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152086 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000341 AC: 85 AN: 249262 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135232

Gnomad AFR exome AF: 0.00439

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 83 AN XY: 727134

Gnomad4 AFR exome AF: 0.00415

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152204 Hom.: 1 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74412

Gnomad4 AFR AF: 0.00511

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000163 Hom.: 1

Bravo AF: 0.00169

ESP6500AA AF: 0.00402 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000405 AC: 49

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CHARGE association Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2021

This variant is associated with the following publications: (PMID: 25107291) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.093	T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.61	N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.16	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.031	B;.;.
Vest4		0.17
MVP		0.64
MPC		0.10
ClinPred		0.0098	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.20

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: rs200898742; hg19: chr8-61654703; COSMIC: COSV71110314; COSMIC: COSV71110314;