rs121912796

Positions:

• chr2-174824464-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The ENST00000409900.9(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. 12/21 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 ENST00000409900.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a zinc_finger_region Phorbol-ester/DAG-type (size 50) in uniprot entity CHIN_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000409900.9
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 17554.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHN1	NM_001822.7	c.682G>A	p.Gly228Ser	missense_variant	8/13	ENST00000409900.9	NP_001813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHN1	ENST00000409900.9	c.682G>A	p.Gly228Ser	missense_variant	8/13	1	NM_001822.7	ENSP00000386741	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Duane retraction syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 08, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;D;.;T;D;D;D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.;.;.;.;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.046	D;T;T;D;.;T;.;T;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.85
MutPred		0.69		Gain of helix (P = 0.0128);.;.;.;.;.;.;.;.;
MVP		0.84
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.85

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

Other links and lift over

dbSNP: rs121912796; hg19: chr2-175689192;