Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_001822.7(CHN1):c.422C>T(p.Pro141Leu) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

CHN1
NM_001822.7 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.66

Publications

3 publications found

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]

CHN1 Gene-Disease associations (from GenCC):

Duane retraction syndrome 2
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
Duane retraction syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CHN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001822.7

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.2662 (below the threshold of 3.09). Trascript score misZ: 1.5101 (below the threshold of 3.09). GenCC associations: The gene is linked to Duane retraction syndrome, Duane retraction syndrome 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

PP5

Variant 2-174877967-G-A is Pathogenic according to our data. Variant chr2-174877967-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29623.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001822.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHN1	NM_001822.7	MANE Select	c.422C>T	p.Pro141Leu	missense	Exon 6 of 13	NP_001813.1
CHN1	NM_001371514.1		c.473C>T	p.Pro158Leu	missense	Exon 6 of 13	NP_001358443.1
CHN1	NM_001371513.1		c.422C>T	p.Pro141Leu	missense	Exon 7 of 14	NP_001358442.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHN1	ENST00000409900.9	TSL:1 MANE Select	c.422C>T	p.Pro141Leu	missense	Exon 6 of 13	ENSP00000386741.4
CHN1	ENST00000488080.6	TSL:1	n.115-2102C>T		intron	N/A
CHN1	ENST00000409156.7	TSL:2	c.422C>T	p.Pro141Leu	missense	Exon 7 of 13	ENSP00000386470.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249256

AF XY:

0.00000740

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000530

Hom.:

ExAC

AF:

0.00000827

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Duane retraction syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.3

PhyloP100

9.7

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.48

Sift

Benign

0.14

Sift4G

Benign

0.079

Polyphen

0.95

Vest4

0.96

MutPred

0.60

Gain of ubiquitination at K136 (P = 0.0695)

MVP

0.50

MPC

1.0

ClinPred

0.95

GERP RS

5.7

Varity_R

0.44

gMVP

0.81

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs387906599

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over