15-92901296-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_001271.4(CHD2):c.59C>T(p.Ser20Leu) variant causes a missense 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S20W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.45

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
• BP6: Variant 15-92901296-C-T is Benign according to our data. Variant chr15-92901296-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 760564.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.59C>T	p.Ser20Leu	missense_variant	2/39	ENST00000394196.9
CHD2	NM_001042572.3	c.59C>T	p.Ser20Leu	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.59C>T	p.Ser20Leu	missense_variant	2/39	5	NM_001271.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445706 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 720024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	0.14	T;T;T;.;.;T;T
Polyphen		1.0	.;D;D;.;.;.;.
Vest4		0.49, 0.49, 0.80, 0.90, 0.59, 0.53
MutPred		0.17		Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);
MVP		0.81
MPC		0.42
ClinPred		0.74	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1057524801; hg19: chr15-93444526;