7-29509310-A-G

Variant names:

• chr7-29509310-A-G
• rs147471814
• NM_004067.4:c.1139A>G

Variant summary

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

The NM_004067.4(CHN2):​c.1139A>G​(p.Asn380Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000373 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: CHN2 NM_004067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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]

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=0.110610574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHN2	NM_004067.4	c.1139A>G	p.Asn380Ser	missense_variant	Exon 12 of 13	ENST00000222792.11	NP_004058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHN2	ENST00000222792.11	c.1139A>G	p.Asn380Ser	missense_variant	Exon 12 of 13	1	NM_004067.4	ENSP00000222792.7

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251400 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135876

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000391 AC: 572 AN: 1461182 Hom.: 0 Cov.: 30 AF XY: 0.000400 AC XY: 291 AN XY: 726940

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000497

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74382

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000398 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1139A>G (p.N380S) alteration is located in exon 12 (coding exon 12) of the CHN2 gene. This alteration results from a A to G substitution at nucleotide position 1139, causing the asparagine (N) at amino acid position 380 to be replaced by a serine (S). 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	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T;.;.;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;L;.;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	.;N;.;N;.;.
REVEL	Benign	0.087
Sift	Benign	0.25	.;T;.;T;.;.
Sift4G	Benign	0.13	.;T;T;T;T;T
Polyphen		0.47, 0.0	.;P;.;.;B;B
Vest4		0.28, 0.25, 0.29, 0.31, 0.27
MVP		0.35
MPC		0.47
ClinPred		0.091	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147471814; hg19: chr7-29548926;