rs1060503522

chr15-92901281-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001271.4(CHD2):c.44T>C(p.Leu15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L15R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.1506235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.44T>C	p.Leu15Pro	missense_variant	2/39	ENST00000394196.9
CHD2	NM_001042572.3	c.44T>C	p.Leu15Pro	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.44T>C	p.Leu15Pro	missense_variant	2/39	5	NM_001271.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Invitae

Sep 04, 2016

This sequence change replaces leucine with proline at codon 15 of the CHD2 protein (p.Leu15Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CHD2-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	23
Dann	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.30	T;T;T;.;.;T;T
Polyphen		0.0	.;B;B;.;.;.;.
Vest4		0.16, 0.16, 0.12, 0.30, 0.22, 0.14
MutPred		0.21		Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);
MVP		0.74
MPC		0.77
ClinPred		0.33	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.14

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: rs1060503522; hg19: chr15-93444511;