Genetic Variant NM_001822.7:c.682G>A (chr2-174824464-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_001822.7(CHN1):c.682G>A(p.Gly228Ser) 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. 13/22 in silico tools predict a damaging 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: 7.91

Publications

4 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:

ENSG00000236449 (HGNC:):

ENSG00000236449 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

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, 0.901

PP5

Variant 2-174824464-C-T is Pathogenic according to our data. Variant chr2-174824464-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17554.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.682G>A	p.Gly228Ser	missense	Exon 8 of 13	NP_001813.1
CHN1	NM_001371514.1		c.733G>A	p.Gly245Ser	missense	Exon 8 of 13	NP_001358443.1
CHN1	NM_001371513.1		c.682G>A	p.Gly228Ser	missense	Exon 9 of 14	NP_001358442.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHN1	ENST00000409900.9	TSL:1 MANE Select	c.682G>A	p.Gly228Ser	missense	Exon 8 of 13	ENSP00000386741.4
CHN1	ENST00000295497.13	TSL:1	c.307G>A	p.Gly103Ser	missense	Exon 2 of 7	ENSP00000295497.7
CHN1	ENST00000488080.6	TSL:1	n.325G>A		non_coding_transcript_exon	Exon 4 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Duane retraction syndrome 2

Pathogenic:1

Aug 08, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

PhyloP100

7.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.046

Polyphen

1.0

Vest4

0.85

MutPred

0.69

Gain of helix (P = 0.0128)

MVP

0.84

MPC

1.0

ClinPred

1.0

GERP RS

5.4

Varity_R

0.98

gMVP

0.85

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over