7-29499881-G-C

Variant names:

• chr7-29499881-G-C
• rs140638672
• NM_004067.4:c.754G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004067.4(CHN2):​c.754G>C​(p.Val252Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,445,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V252I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CHN2 NM_004067.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.77
• Publications: 0 publications found

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]

PRR15-DT (HGNC:55866): (PRR15 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004067.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHN2	NM_004067.4	MANE Select	c.754G>C	p.Val252Leu	missense	Exon 9 of 13	NP_004058.1	P52757-1
	CHN2	NM_001293070.2		c.793G>C	p.Val265Leu	missense	Exon 10 of 14	NP_001279999.1	B7Z1V0
	CHN2	NM_001293072.2		c.709G>C	p.Val237Leu	missense	Exon 9 of 13	NP_001280001.1	B7Z1W9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHN2	ENST00000222792.11	TSL:1 MANE Select	c.754G>C	p.Val252Leu	missense	Exon 9 of 13	ENSP00000222792.7	P52757-1
	CHN2	ENST00000409041.8	TSL:1	c.346G>C	p.Val116Leu	missense	Exon 3 of 5	ENSP00000386849.5	B3VCF5
	CHN2	ENST00000439711.7	TSL:1	c.346G>C	p.Val116Leu	missense	Exon 3 of 5	ENSP00000387425.3	B3VCF6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 237892 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1445880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718520

African (AFR) AF: 0.00 AC: 0 AN: 32832

American (AMR) AF: 0.00 AC: 0 AN: 41030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 82534

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106256

Other (OTH) AF: 0.0000167 AC: 1 AN: 59724

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.049	D
Polyphen		0.99	D
Vest4		0.64
MutPred		0.67		Loss of methylation at K329 (P = 0.0767)
MVP		0.97
MPC		1.0
ClinPred		0.91	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.76
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs140638672; hg19: chr7-29539497;