2-174800088-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001822.7(CHN1):c.*28T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,520,466 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (8 hom.)
• Consequence: CHN1 NM_001822.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.580

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-174800088-A-G is Benign according to our data. Variant chr2-174800088-A-G is described in ClinVar as [Benign]. Clinvar id is 332461.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00548 (835/152320) while in subpopulation AFR AF= 0.0191 (795/41564). AF 95% confidence interval is 0.018. There are 3 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 832 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHN1	NM_001822.7	c.*28T>C		3_prime_UTR_variant	13/13	ENST00000409900.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHN1	ENST00000409900.9	c.*28T>C		3_prime_UTR_variant	13/13	1	NM_001822.7	P1

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152202 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00137 AC: 197 AN: 143586 Hom.: 3 AF XY: 0.00109 AC XY: 83 AN XY: 75848

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000536

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.000629 AC: 860 AN: 1368146 Hom.: 8 Cov.: 27 AF XY: 0.000609 AC XY: 411 AN XY: 674722

Gnomad4 AFR exome AF: 0.0236

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000113

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00548 AC: 835 AN: 152320 Hom.: 3 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74490

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00252 Hom.: 2

Bravo AF: 0.00679

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duane retraction syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	8.8
Dann	Benign	0.84

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: rs143852940; hg19: chr2-175664816;