2-174812294-C-T

Variant names:

• chr2-174812294-C-T
• rs12613075
• NM_001822.7:c.886+15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001822.7(CHN1):​c.886+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,596,542 control chromosomes in the GnomAD database, including 178,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (12129 hom., cov: 32)
  • Exomes 𝑓: 0.47 (166365 hom.)
• Consequence: CHN1 NM_001822.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0350
• 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

ENSG00000236449 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-174812294-C-T is Benign according to our data. Variant chr2-174812294-C-T is described in ClinVar as Benign. ClinVar VariationId is 332464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHN1	NM_001822.7	c.886+15G>A		intron_variant	Intron 9 of 12	ENST00000409900.9	NP_001813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHN1	ENST00000409900.9	c.886+15G>A		intron_variant	Intron 9 of 12	1	NM_001822.7	ENSP00000386741.4

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55351 AN: 151954 Hom.: 12137 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.382

GnomAD2 exomes AF: 0.426 AC: 103784 AN: 243890 AF XY: 0.440

Gnomad AFR exome AF: 0.0981

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.459

Gnomad FIN exome AF: 0.470

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.473 AC: 683267 AN: 1444470 Hom.: 166365 Cov.: 33 AF XY: 0.476 AC XY: 340547 AN XY: 716138

African (AFR) AF: 0.0936 AC: 3109 AN: 33228

American (AMR) AF: 0.256 AC: 11312 AN: 44110

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 10324 AN: 25534

East Asian (EAS) AF: 0.439 AC: 17318 AN: 39410

South Asian (SAS) AF: 0.490 AC: 40967 AN: 83566

European-Finnish (FIN) AF: 0.473 AC: 25034 AN: 52976

Middle Eastern (MID) AF: 0.443 AC: 2509 AN: 5662

European-Non Finnish (NFE) AF: 0.496 AC: 545512 AN: 1100410

Other (OTH) AF: 0.456 AC: 27182 AN: 59574

GnomAD4 genome AF: 0.364 AC: 55336 AN: 152072 Hom.: 12129 Cov.: 32 AF XY: 0.365 AC XY: 27153 AN XY: 74344

African (AFR) AF: 0.109 AC: 4543 AN: 41508

American (AMR) AF: 0.316 AC: 4832 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1444 AN: 3468

East Asian (EAS) AF: 0.450 AC: 2325 AN: 5170

South Asian (SAS) AF: 0.495 AC: 2388 AN: 4820

European-Finnish (FIN) AF: 0.472 AC: 4983 AN: 10556

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.491 AC: 33375 AN: 67952

Other (OTH) AF: 0.379 AC: 799 AN: 2106

Alfa AF: 0.440 Hom.: 7812

Bravo AF: 0.339

Asia WGS AF: 0.476 AC: 1657 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duane retraction syndrome 2 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.1
DANN	Benign	0.38
PhyloP100		0.035
Mutation Taster		=100/0	polymorphism (auto)

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: rs12613075; hg19: chr2-175677022;