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rs121912797

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_001822.7(CHN1):c.755C>A(p.Pro252Gln) variant causes a missense 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. 12/21 in silico tools predict a damaging 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. P252S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CHN1
NM_001822.7 missense

Scores

15
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.94
Variant links:
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 9 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 chr2-174812441-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29624.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.883
PP5
Variant 2-174812440-G-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHN1NM_001822.7 linkuse as main transcriptc.755C>A p.Pro252Gln missense_variant 9/13 ENST00000409900.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHN1ENST00000409900.9 linkuse as main transcriptc.755C>A p.Pro252Gln missense_variant 9/131 NM_001822.7 P1P15882-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
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 providedliterature onlyOMIMAug 08, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
Cadd
Pathogenic
31
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D;.;D;.;T;D;D;D;T
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D;D;D;.;.;.;.;.
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Pathogenic
3.0
M;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-6.6
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.011
D;D;D;D;.;D;.;D;.
Polyphen
0.95
P;D;.;.;.;.;.;.;.
Vest4
0.58
MutPred
0.51
Gain of ubiquitination at K256 (P = 0.0561);.;.;.;.;.;.;.;.;
MVP
0.66
MPC
0.79
ClinPred
0.99
D
GERP RS
6.0
Varity_R
0.85
gMVP
0.74

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121912797; hg19: chr2-175677168; API