rs766862122

chr8-60852924-C-Gchr8-60852924-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1 PP2 BP6_Very_Strong BS2

The NM_017780.4(CHD7):c.6199C>G(p.Gln2067Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.90

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 -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_017780.4
• PP2: Missense variant where missense usually causes diseases, CHD7
• BP6: Variant 8-60852924-C-G is Benign according to our data. Variant chr8-60852924-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 260912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.6199C>G	p.Gln2067Glu	missense_variant	31/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.6199C>G	p.Gln2067Glu	missense_variant	31/38	5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-9305C>G		intron_variant		1
CHD7	ENST00000695853.1	c.6199C>G	p.Gln2067Glu	missense_variant, NMD_transcript_variant	31/37

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249228 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461712 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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 09, 2021

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	0.18
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.069
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.44
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.020	B
Vest4		0.68
MutPred		0.27		Loss of MoRF binding (P = 0.0381);
MVP		0.87
MPC		0.65
ClinPred		0.34	T
GERP RS		5.4
Varity_R		0.34
gMVP		0.45

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: rs766862122; hg19: chr8-61765483;