chr15-92981389-C-T

Variant names:

• chr15-92981389-C-T
• rs758134774
• NM_001271.4:c.2998C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PP2 PP3 BP6_Moderate

The NM_001271.4(CHD2):​c.2998C>T​(p.Arg1000Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.60

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CHD2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 57 curated pathogenic missense variants (we use a threshold of 10). The gene has 104 curated benign missense variants. Gene score misZ: 5.2052 (above the threshold of 3.09). Trascript score misZ: 6.0204 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 94, complex neurodevelopmental disorder, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77
• BP6: Variant 15-92981389-C-T is Benign according to our data. Variant chr15-92981389-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474380.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD2	NM_001271.4	c.2998C>T	p.Arg1000Trp	missense_variant	Exon 24 of 39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.2998C>T	p.Arg1000Trp	missense_variant	Exon 24 of 39	5	NM_001271.4	ENSP00000377747.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460668 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726642

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Benign:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.45		Loss of disorder (P = 6e-04);Loss of disorder (P = 6e-04);
MVP		0.60
MPC		2.6
ClinPred		0.79	D
GERP RS		4.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.44
gMVP		0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs758134774; hg19: chr15-93524619; COSMIC: COSV67712076; COSMIC: COSV67712076;