19-1037725-C-G

Variant names:

• chr19-1037725-C-G
• rs770742226
• NM_004368.4:c.755C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004368.4(CNN2):​c.755C>G​(p.Thr252Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. T252M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 39)
• Consequence: CNN2 NM_004368.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54
• Publications: 0 publications found

Genes affected

CNN2 (HGNC:2156): (calponin 2) The protein encoded by this gene, which can bind actin, calmodulin, troponin C, and tropomyosin, may function in the structural organization of actin filaments. The encoded protein could play a role in smooth muscle contraction and cell adhesion. Several pseudogenes of this gene have been identified, and are present on chromosomes 1, 2, 3, 6, 9, 11, 13, 15, 16, 21 and 22. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.15171 (below the threshold of 3.09). Trascript score misZ: 0.22112 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.24701273).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004368.4. 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
	CNN2	NM_004368.4	MANE Select	c.755C>G	p.Thr252Arg	missense	Exon 7 of 7	NP_004359.1	Q99439-1
	CNN2	NM_001303501.2		c.818C>G	p.Thr273Arg	missense	Exon 7 of 7	NP_001290430.1	B4DUT8
	CNN2	NM_001303499.2		c.722C>G	p.Thr241Arg	missense	Exon 7 of 7	NP_001290428.1	B4DDF4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNN2	ENST00000263097.9	TSL:1 MANE Select	c.755C>G	p.Thr252Arg	missense	Exon 7 of 7	ENSP00000263097.2	Q99439-1
	CNN2	ENST00000562958.6	TSL:2	c.818C>G	p.Thr273Arg	missense	Exon 7 of 7	ENSP00000456436.1	B4DUT8
	CNN2	ENST00000926772.1		c.749C>G	p.Thr250Arg	missense	Exon 7 of 7	ENSP00000596831.1

Frequencies

GnomAD3 genomes Cov.: 39

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 39

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.048	B
Vest4		0.096
MutPred		0.49		Gain of MoRF binding (P = 0.0438)
MVP		0.52
MPC		0.41
ClinPred		0.79	D
GERP RS		3.2
Varity_R		0.16
gMVP		0.46
Mutation Taster		=87/13	polymorphism

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: rs770742226; hg19: chr19-1037724;