Genetic Variant CHD5:p.Gly1948Val (chr1-6106409-C-A) – 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.5843G>T(p.Gly1948Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,112 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1948E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CHD5
NM_015557.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.46

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CHD5 links:

Genome browser will be placed here

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, 0.901

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015557.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD5	NM_015557.3	MANE Select	c.5843G>T	p.Gly1948Val	missense	Exon 40 of 42	NP_056372.1	Q8TDI0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD5	ENST00000262450.8	TSL:1 MANE Select	c.5843G>T	p.Gly1948Val	missense	Exon 40 of 42	ENSP00000262450.3	Q8TDI0
CHD5	ENST00000496404.1	TSL:2	n.*883G>T		non_coding_transcript_exon	Exon 32 of 34	ENSP00000433676.1	F2Z2R5
CHD5	ENST00000496404.1	TSL:2	n.*883G>T		3_prime_UTR	Exon 32 of 34	ENSP00000433676.1	F2Z2R5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000470

AC:

AN:

212870

AF XY:

0.00000865

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442112

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33028

American (AMR)

AF:

0.00

AC:

AN:

41208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

38498

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102988

Other (OTH)

AF:

0.00

AC:

AN:

59656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000834

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.92

MutationAssessor

Benign

0.90

PhyloP100

7.5

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Benign

0.082

Polyphen

1.0

Vest4

0.94

MutPred

0.56

Loss of disorder (P = 0.0439)

MVP

0.91

MPC

1.7

ClinPred

1.0

GERP RS

4.9

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.79

gMVP

0.71

Mutation Taster

=39/61

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over