NM_004067.4:c.871C>T

Variant names:

• chr7-29499998-C-T
• NM_004067.4:c.871C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004067.4(CHN2):​c.871C>T​(p.Pro291Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHN2 NM_004067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

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.871C>T	p.Pro291Ser	missense	Exon 9 of 13	NP_004058.1	P52757-1
	CHN2	NM_001293070.2		c.910C>T	p.Pro304Ser	missense	Exon 10 of 14	NP_001279999.1	B7Z1V0
	CHN2	NM_001293072.2		c.826C>T	p.Pro276Ser	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.871C>T	p.Pro291Ser	missense	Exon 9 of 13	ENSP00000222792.7	P52757-1
	CHN2	ENST00000409041.8	TSL:1	c.463C>T	p.Pro155Ser	missense	Exon 3 of 5	ENSP00000386849.5	B3VCF5
	CHN2	ENST00000439711.7	TSL:1	c.463C>T	p.Pro155Ser	missense	Exon 3 of 5	ENSP00000387425.3	B3VCF6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.66
Sift	Benign	0.051	T
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Gain of helix (P = 0.0425)
MVP		0.91
MPC		1.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.93
Mutation Taster		=5/95	disease causing

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

Other links and lift over

hg19: chr7-29539614;