15-92992976-G-T

Variant names:

• chr15-92992976-G-T
• NM_001271.4:c.3573G>T

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.3573G>T​(p.Gln1191His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1191Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10881898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD2	NM_001271.4	c.3573G>T	p.Gln1191His	missense_variant	Exon 28 of 39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.3573G>T	p.Gln1191His	missense_variant	Exon 28 of 39	5	NM_001271.4	ENSP00000377747.4
CHD2	ENST00000637789.1	n.*148G>T		non_coding_transcript_exon_variant	Exon 5 of 9	5		ENSP00000489767.1
CHD2	ENST00000637789.1	n.*148G>T		3_prime_UTR_variant	Exon 5 of 9	5		ENSP00000489767.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461580 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.20	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.92	.;N
REVEL	Benign	0.17
Sift	Benign	0.13	.;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0020	B;B
Vest4		0.12
MutPred		0.22		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.67
MPC		1.3
ClinPred		0.24	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.53

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-93536206;