15-92901240-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001271.4(CHD2):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

CHD2
NM_001271.4 start_lost

Scores

5
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.44
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 CDS bases. Genomic position: 92901240. Lost 0.001 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHD2NM_001271.4 linkc.3G>T p.Met1? start_lost Exon 2 of 39 ENST00000394196.9 NP_001262.3 O14647-1
CHD2NM_001042572.3 linkc.3G>T p.Met1? start_lost Exon 2 of 13 NP_001036037.1 O14647-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHD2ENST00000394196.9 linkc.3G>T p.Met1? start_lost Exon 2 of 39 5 NM_001271.4 ENSP00000377747.4 O14647-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
26
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
May 13, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; however downstream Methionine is observed and functional data is not available to determine whether this variant is disruptive in this transcript; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.082
.;.;T;.;.;T;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.12
D
PROVEAN
Benign
-0.77
.;.;N;.;.;.;N
REVEL
Uncertain
0.44
Sift
Pathogenic
0.0
.;.;D;.;.;.;D
Sift4G
Pathogenic
0.0
D;T;T;.;.;T;T
Polyphen
0.23, 0.15
.;B;B;.;.;.;.
Vest4
0.86, 0.92, 0.86, 0.92, 0.86, 0.91
MutPred
0.98
Gain of catalytic residue at M1 (P = 0.0576);Gain of catalytic residue at M1 (P = 0.0576);Gain of catalytic residue at M1 (P = 0.0576);Gain of catalytic residue at M1 (P = 0.0576);Gain of catalytic residue at M1 (P = 0.0576);Gain of catalytic residue at M1 (P = 0.0576);Gain of catalytic residue at M1 (P = 0.0576);
MVP
0.70
ClinPred
0.85
D
GERP RS
6.0
Varity_R
0.81
gMVP
0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-93444470; API