chr7-29292923-A-T

Position:

• chr7-29292923-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_001293070.2(CHN2):​c.50-2A>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 456,194 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (14 hom.)
• Consequence: CHN2 NM_001293070.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00002634
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0100

Genes affected

CHN2 (HGNC:1944): (chimerin 2) This gene encodes a guanosine triphosphate (GTP)-metabolizing protein that contains a phorbol-ester/diacylglycerol (DAG)-type zinc finger, a Rho-GAP domain, and an SH2 domain. The encoded protein translocates from the cytosol to the Golgi apparatus membrane upon binding by diacylglycerol (DAG). Activity of this protein is important in cell proliferation and migration, and expression changes in this gene have been detected in cancers. A mutation in this gene has also been associated with schizophrenia in men. Alternative transcript splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, May 2014]

CHN2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.026279392 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of 16, new splice context is: tctgtctattctgaacccAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 7-29292923-A-T is Benign according to our data. Variant chr7-29292923-A-T is described in ClinVar as [Benign]. Clinvar id is 3038773.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0145 (2207/152218) while in subpopulation AFR AF= 0.0496 (2059/41508). AF 95% confidence interval is 0.0478. There are 56 homozygotes in gnomad4. There are 1054 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHN2	NM_004067.4	c.50-61702A>T		intron_variant		ENST00000222792.11	NP_004058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHN2	ENST00000222792.11	c.50-61702A>T		intron_variant		1	NM_004067.4	ENSP00000222792.7

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2207 AN: 152100 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

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: 0.000235

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00354 AC: 455 AN: 128414 Hom.: 10 AF XY: 0.00267 AC XY: 188 AN XY: 70326

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.00300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00205 AC: 623 AN: 303976 Hom.: 14 Cov.: 0 AF XY: 0.00146 AC XY: 253 AN XY: 173080

Gnomad4 AFR exome AF: 0.0535

Gnomad4 AMR exome AF: 0.00312

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000201

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.0145 AC: 2207 AN: 152218 Hom.: 56 Cov.: 32 AF XY: 0.0142 AC XY: 1054 AN XY: 74412

Gnomad4 AFR AF: 0.0496

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.000995 Hom.: 0

Bravo AF: 0.0171

ExAC AF: 0.00156 AC: 24

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CHN2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.54
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.057	N
GERP RS		-0.013

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.19		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: rs115892746; hg19: chr7-29332539;