chr19-1037830-C-G

Variant names:

• chr19-1037830-C-G
• rs577706819
• NM_004368.4:c.860C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004368.4(CNN2):​c.860C>G​(p.Thr287Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T287A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 38)
• Consequence: CNN2 NM_004368.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.288

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04978338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNN2	NM_004368.4	c.860C>G	p.Thr287Ser	missense_variant	Exon 7 of 7	ENST00000263097.9	NP_004359.1
CNN2	NM_001303501.2	c.923C>G	p.Thr308Ser	missense_variant	Exon 7 of 7		NP_001290430.1
CNN2	NM_001303499.2	c.827C>G	p.Thr276Ser	missense_variant	Exon 7 of 7		NP_001290428.1
CNN2	NM_201277.3	c.743C>G	p.Thr248Ser	missense_variant	Exon 6 of 6		NP_958434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNN2	ENST00000263097.9	c.860C>G	p.Thr287Ser	missense_variant	Exon 7 of 7	1	NM_004368.4	ENSP00000263097.2

Frequencies

GnomAD3 genomes Cov.: 38

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 38

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.860C>G (p.T287S) alteration is located in exon 7 (coding exon 7) of the CNN2 gene. This alteration results from a C to G substitution at nucleotide position 860, causing the threonine (T) at amino acid position 287 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	0.063
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.7
DANN	Benign	0.65
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.28	T;T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.050	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0090	B;.;B;B
Vest4		0.061
MutPred		0.15		.;.;.;Gain of phosphorylation at S306 (P = 0.1404);
MVP		0.22
MPC		0.088
ClinPred		0.25	T
GERP RS		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.19

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: rs577706819; hg19: chr19-1037829;