chr2-174812441-G-A
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_001822.7(CHN1):c.754C>T(p.Pro252Ser) variant causes a missense change. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P252Q) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
CHN1
NM_001822.7 missense
NM_001822.7 missense
Scores
7
10
2
Clinical Significance
Conservation
PhyloP100: 5.70
Genes affected
CHN1 (HGNC:1943): (chimerin 1) This gene encodes GTPase-activating protein for ras-related p21-rac and a phorbol ester receptor. It is predominantly expressed in neurons, and plays an important role in neuronal signal-transduction mechanisms. Mutations in this gene are associated with Duane's retraction syndrome 2 (DURS2). Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a zinc_finger_region Phorbol-ester/DAG-type (size 50) in uniprot entity CHIN_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001822.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-174812440-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 17555.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.745
PP5
Variant 2-174812441-G-A is Pathogenic according to our data. Variant chr2-174812441-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29624.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHN1 | NM_001822.7 | c.754C>T | p.Pro252Ser | missense_variant | 9/13 | ENST00000409900.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHN1 | ENST00000409900.9 | c.754C>T | p.Pro252Ser | missense_variant | 9/13 | 1 | NM_001822.7 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Duane retraction syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D;.;T;D;D;D;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;.;.;.;.;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;T;D;T;T;T
Sift4G
Benign
T;T;T;T;.;T;.;T;.
Polyphen
B;P;.;.;.;.;.;.;.
Vest4
MutPred
Gain of ubiquitination at K256 (P = 0.07);.;.;.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at