rs61752830
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_ModerateBP6_ModerateBS2
The NM_001271.4(CHD2):c.4978G>A(p.Asp1660Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,990 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 Likely benign (★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
CHD2
NM_001271.4 missense
NM_001271.4 missense
Scores
1
7
7
Clinical Significance
Conservation
PhyloP100: 7.68
Genes affected
CHD2 (HGNC:1917): (chromodomain helicase DNA binding protein 2) The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, CHD2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2166372).
BP6
?
Variant 15-93020083-G-A is Benign according to our data. Variant chr15-93020083-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238884.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
?
High AC in GnomAd at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD2 | NM_001271.4 | c.4978G>A | p.Asp1660Asn | missense_variant | 38/39 | ENST00000394196.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD2 | ENST00000394196.9 | c.4978G>A | p.Asp1660Asn | missense_variant | 38/39 | 5 | NM_001271.4 | P1 | |
CHD2 | ENST00000626874.2 | c.4978G>A | p.Asp1660Asn | missense_variant | 38/38 | 1 | |||
CHD2 | ENST00000625662.3 | c.*1149G>A | 3_prime_UTR_variant, NMD_transcript_variant | 34/35 | 5 | ||||
CHD2 | ENST00000627460.1 | c.*110G>A | 3_prime_UTR_variant, NMD_transcript_variant | 4/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152102Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251420Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135878
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GnomAD4 exome AF: 0.000114 AC: 167AN: 1461888Hom.: 0 Cov.: 35 AF XY: 0.000106 AC XY: 77AN XY: 727246
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHD2 p.Asp1660Asn variant was not identified in the literature but was identified in dbSNP (ID: rs61752830) and ClinVar (classified as uncertain significance by Invitae for Epileptic encephalopathy, childhood-onset). The variant was identified in control databases in 10 of 282816 chromosomes at a frequency of 0.00003536 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7220 chromosomes (freq: 0.000139), European (non-Finnish) in 8 of 129150 chromosomes (freq: 0.000062) and African in 1 of 24962 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. This frequency is greater than expected for rare autosomal dominant CHD2-related neurodevelopmental disorders. The p.Asp1660 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Developmental and epileptic encephalopathy 94 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;D
Polyphen
P;P
Vest4
MVP
MPC
0.26
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at