chr16-53156969-G-C

Position:

• chr16-53156969-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001308319.2(CHD9):​c.880G>C​(p.Ala294Pro) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD9 NM_001308319.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.968

Genes affected

CHD9 (HGNC:25701): (chromodomain helicase DNA binding protein 9) Predicted to enable ATP binding activity; ATP-dependent activity, acting on DNA; and DNA binding activity. Predicted to be involved in DNA duplex unwinding and chromatin organization. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CHD9 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13592955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD9	NM_001308319.2	c.880G>C	p.Ala294Pro	missense_variant	2/39	ENST00000447540.6	NP_001295248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD9	ENST00000447540.6	c.880G>C	p.Ala294Pro	missense_variant	2/39	5	NM_001308319.2	ENSP00000396345.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248572 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2024

The c.880G>C (p.A294P) alteration is located in exon 2 (coding exon 1) of the CHD9 gene. This alteration results from a G to C substitution at nucleotide position 880, causing the alanine (A) at amino acid position 294 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T;.;T;.;T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T;.;T;T;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.34	N;N;.;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.38	N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.61	P;P;.;P;P
Vest4		0.16
MutPred		0.14		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.65
MPC		0.24
ClinPred		0.31	T
GERP RS		2.8
Varity_R		0.11
gMVP		0.55

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: rs765814836; hg19: chr16-53190881;