Genetic Variant CHD5:p.Asn793Lys (chr1-6142185-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015557.3(CHD5):c.2379C>A(p.Asn793Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CHD5
NM_015557.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.280

Publications

0 publications found

Variant links:

Genes affected

CHD5 (HGNC:16816): (chromodomain helicase DNA binding protein 5) This gene encodes a member of the chromodomain helicase DNA-binding protein family. Members of this family are characterized by a chromodomain, a helicase ATP-binding domain and an additional functional domain. This gene encodes a neuron-specific protein that may function in chromatin remodeling and gene transcription. This gene is a potential tumor suppressor gene that may play a role in the development of neuroblastoma. [provided by RefSeq, Feb 2012]

CHD5 Gene-Disease associations (from GenCC):

parenti-mignot neurodevelopmental syndrome
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CHD5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD5	NM_015557.3 link	c.2379C>A	p.Asn793Lys	missense_variant	Exon 15 of 42	ENST00000262450.8	NP_056372.1	Q8TDI0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHD5	ENST00000262450.8 link	c.2379C>A	p.Asn793Lys	missense_variant	Exon 15 of 42	1	NM_015557.3	ENSP00000262450.3	Q8TDI0
CHD5	ENST00000462991.5 link	n.525C>A		non_coding_transcript_exon_variant	Exon 4 of 31	1		ENSP00000466706.1	K7EMY3
CHD5	ENST00000496404.1 link	n.2379C>A		non_coding_transcript_exon_variant	Exon 15 of 34	2		ENSP00000433676.1	F2Z2R5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

0.70

PhyloP100

-0.28

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.55

Sift

Benign

0.074

Sift4G

Uncertain

0.056

Polyphen

1.0

Vest4

0.90

MutPred

0.54

Gain of ubiquitination at N793 (P = 0.0104);

MVP

0.91

MPC

2.3

ClinPred

0.99

GERP RS

-4.8

Varity_R

0.43

gMVP

0.97

Mutation Taster

=15/85

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over