chr2-174824485-A-G

Variant names:

• chr2-174824485-A-G
• rs1553475005
• NM_001822.7:c.661T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PP2 PP5_Moderate BP4

The NM_001822.7(CHN1):​c.661T>C​(p.Tyr221His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHN1 NM_001822.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.04
• Publications: 1 publications found

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

ENSG00000236449 (HGNC:):

ACMG classification

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

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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.
• PP5: Variant 2-174824485-A-G is Pathogenic according to our data. Variant chr2-174824485-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 559835.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41849428). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHN1	NM_001822.7	c.661T>C	p.Tyr221His	missense_variant	Exon 8 of 13	ENST00000409900.9	NP_001813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHN1	ENST00000409900.9	c.661T>C	p.Tyr221His	missense_variant	Exon 8 of 13	1	NM_001822.7	ENSP00000386741.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Duane retraction syndrome 2 Pathogenic:1

Apr 10, 2017

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.(Tyr221His) variant in CHN1 has never been reported, and was absent frome large population studies. It is considered as pathogenic according to ACMG classification. Additionally, segregation analysis is consistent with the phenotype. -

not provided Pathogenic:1

-

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;D;.;D;D;D
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D;D;.;.;.
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	-0.41	N;.;.;.;.;.;.
PhyloP100		5.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.13	T;T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;.;T;.
Polyphen		0.71	P;B;.;.;.;.;.
Vest4		0.27
MutPred		0.59		Gain of helix (P = 0.0199);.;.;.;.;.;.;
MVP		0.34
MPC		0.53
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.70
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553475005; hg19: chr2-175689213;