7-29194958-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004067.4(CHN2):c.17A>C(p.Asn6Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000785 in 1,582,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: CHN2 NM_004067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17

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]

CPVL (HGNC:14399): (carboxypeptidase vitellogenic like) The protein encoded by this gene is a carboxypeptidase and bears strong sequence similarity to serine carboxypeptidases. Carboxypeptidases are a large class of proteases that act to cleave a single amino acid from the carboxy termini of proteins or peptides. The exact function of this protein, however, has not been determined. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15196893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHN2	NM_004067.4	c.17A>C	p.Asn6Thr	missense_variant	1/13	ENST00000222792.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHN2	ENST00000222792.11	c.17A>C	p.Asn6Thr	missense_variant	1/13	1	NM_004067.4	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000292 AC: 62 AN: 212464 Hom.: 0 AF XY: 0.000281 AC XY: 33 AN XY: 117504

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000662

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000986

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.000199

GnomAD4 exome AF: 0.000845 AC: 1209 AN: 1430948 Hom.: 1 Cov.: 30 AF XY: 0.000801 AC XY: 570 AN XY: 711662

Gnomad4 AFR exome AF: 0.0000329

Gnomad4 AMR exome AF: 0.0000485

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74326

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000383

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000268

ExAC AF: 0.000357 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.17A>C (p.N6T) alteration is located in exon 1 (coding exon 1) of the CHN2 gene. This alteration results from a A to C substitution at nucleotide position 17, causing the asparagine (N) at amino acid position 6 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	26
Dann	Benign	0.96
DEOGEN2	Benign	0.043	T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	D;D;D;D;N;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.43	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.30	T;D;D
Sift4G	Benign	0.15	T;D;D
Polyphen		0.95	P;.;.
Vest4		0.24
MVP		0.85
MPC		0.99
ClinPred		0.27	T
GERP RS		4.1
Varity_R		0.31
gMVP		0.60

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: rs201909711; hg19: chr7-29234574;