19-1032412-C-T

Variant names:

• chr19-1032412-C-T
• rs199749887
• NM_004368.4:c.206C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004368.4(CNN2):​c.206C>T​(p.Pro69Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CNN2 NM_004368.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNN2	NM_004368.4	c.206C>T	p.Pro69Leu	missense_variant	Exon 3 of 7	ENST00000263097.9	NP_004359.1
CNN2	NM_001303501.2	c.206C>T	p.Pro69Leu	missense_variant	Exon 3 of 7		NP_001290430.1
CNN2	NM_001303499.2	c.206C>T	p.Pro69Leu	missense_variant	Exon 3 of 7		NP_001290428.1
CNN2	NM_201277.3	c.206C>T	p.Pro69Leu	missense_variant	Exon 3 of 6		NP_958434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNN2	ENST00000263097.9	c.206C>T	p.Pro69Leu	missense_variant	Exon 3 of 7	1	NM_004368.4	ENSP00000263097.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251234 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135838

Gnomad AFR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461374 Hom.: 0 Cov.: 46 AF XY: 0.00000688 AC XY: 5 AN XY: 726962

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74306

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.206C>T (p.P69L) alteration is located in exon 3 (coding exon 3) of the CNN2 gene. This alteration results from a C to T substitution at nucleotide position 206, causing the proline (P) at amino acid position 69 to be replaced by a leucine (L). 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	0.28
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;D;.;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;D;T;T;T;D;T;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.8	D;.;D;D;D;.;.;.;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0060	D;.;D;D;D;.;.;.;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;D;D
Polyphen		0.20	B;.;.;B;B;.;.;.;.
Vest4		0.77
MutPred		0.56		Loss of disorder (P = 0.036);.;Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);.;.;.;
MVP		0.98
MPC		0.17
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.74

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: rs199749887; hg19: chr19-1032411;