2-174878011-A-C

Variant names:

• chr2-174878011-A-C
• rs121912793
• NM_001822.7:c.378T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_001822.7(CHN1):​c.378T>G​(p.Ile126Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. I126T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CHN1 NM_001822.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.14
• Publications: 7 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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.
• PP5: Variant 2-174878011-A-C is Pathogenic according to our data. Variant chr2-174878011-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 17551.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37812477). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHN1	NM_001822.7	MANE Select	c.378T>G	p.Ile126Met	missense	Exon 6 of 13	NP_001813.1
	CHN1	NM_001371514.1		c.429T>G	p.Ile143Met	missense	Exon 6 of 13	NP_001358443.1
	CHN1	NM_001371513.1		c.378T>G	p.Ile126Met	missense	Exon 7 of 14	NP_001358442.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHN1	ENST00000409900.9	TSL:1 MANE Select	c.378T>G	p.Ile126Met	missense	Exon 6 of 13	ENSP00000386741.4
	CHN1	ENST00000488080.6	TSL:1	n.115-2146T>G		intron	N/A
	CHN1	ENST00000651246.1		c.-31T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	ENSP00000498484.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.0000242 AC: 1 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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	Benign	0.26
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Benign	0.36
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	0.84	T
Polyphen		0.042	B
Vest4		0.70
MutPred		0.44		Loss of ubiquitination at K129 (P = 0.1278)
MVP		0.84
MPC		0.54
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.35
gMVP		0.70
Mutation Taster		=19/81	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: rs121912793; hg19: chr2-175742739;