rs1555445701

Positions:

• chr15-93014902-TAATGCAG-TT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_001271.4(CHD2):​c.4900_4906delinsT​(p.Asn1634_Asp1636delinsTyr) variant causes a protein altering, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD2 NM_001271.4 protein_altering, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001271.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.4900_4906delinsT	p.Asn1634_Asp1636delinsTyr	protein_altering_variant, splice_region_variant	37/39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.4900_4906delinsT	p.Asn1634_Asp1636delinsTyr	protein_altering_variant, splice_region_variant	37/39	5	NM_001271.4	ENSP00000377747	P1
CHD2	ENST00000626874.2	c.4900_4906delinsT	p.Asn1634_Asp1636delinsTyr	protein_altering_variant, splice_region_variant	37/38	1		ENSP00000486629
CHD2	ENST00000625662.3	c.*1071_*1077delinsT		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	33/35	5		ENSP00000486007
CHD2	ENST00000627460.1	c.*32_*38delinsT		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	3/5	5		ENSP00000485982

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2018

This variant has not been reported in the literature in individuals with CHD2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change deletes 7 nucleotides and inserts 1 nucleotide in exon 37 of the CHD2 gene(c.4900_4906delinsT). This is predicted to result in a deletion of 3 amino acid residues and insertion of 1 amino acid residue in the CHD2 protein (p.Asn1634_Asp1636delinsTyr) but otherwise preserves the integrity of the reading frame. This variant also affects the last nucleotide of exon 37 of the CHD2 coding sequence, which is part of the consensus splice site for this exon. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555445701; hg19: chr15-93558133;