2-174799439-C-T

Position:

• chr2-174799439-C-T

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.*677G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0113 in 462,550 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (12 hom., cov: 33)
  • Exomes 𝑓: 0.012 (46 hom.)
• Consequence: CHN1 NM_001822.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.00

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 2-174799439-C-T is Benign according to our data. Variant chr2-174799439-C-T is described in ClinVar as [Benign]. Clinvar id is 332455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00882 (1341/152118) while in subpopulation SAS AF= 0.0152 (73/4818). AF 95% confidence interval is 0.0124. There are 12 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1341 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHN1	NM_001822.7	c.*677G>A		3_prime_UTR_variant	13/13	ENST00000409900.9	NP_001813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHN1	ENST00000409900	c.*677G>A		3_prime_UTR_variant	13/13	1	NM_001822.7	ENSP00000386741.4
CHN1	ENST00000295497	c.*677G>A		3_prime_UTR_variant	7/7	1		ENSP00000295497.7
CHN1	ENST00000652036	c.*677G>A		3_prime_UTR_variant	8/8			ENSP00000499139.1
CHN1	ENST00000443238.6	c.*677G>A		3_prime_UTR_variant	8/8	4		ENSP00000409798.2

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1342 AN: 152002 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0433

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0114 AC: 1133 AN: 99158 Hom.: 10 AF XY: 0.0116 AC XY: 631 AN XY: 54554

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.00987

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.0134

Gnomad FIN exome AF: 0.00224

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.0125 AC: 3867 AN: 310432 Hom.: 46 Cov.: 0 AF XY: 0.0128 AC XY: 2199 AN XY: 171266

Gnomad4 AFR exome AF: 0.00199

Gnomad4 AMR exome AF: 0.0100

Gnomad4 ASJ exome AF: 0.0426

Gnomad4 EAS exome AF: 0.000120

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.00310

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.00882 AC: 1341 AN: 152118 Hom.: 12 Cov.: 33 AF XY: 0.00830 AC XY: 617 AN XY: 74366

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0433

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0152

Gnomad4 FIN AF: 0.00293

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0114 Hom.: 4

Bravo AF: 0.00929

Asia WGS AF: 0.00578 AC: 20 AN: 3474

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 12, 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	-0.28
CADD	Benign	16
DANN	Benign	0.92

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: rs192645480; hg19: chr2-175664167;