chr19-1032562-G-A

Position:

• chr19-1032562-G-A

Variant summary

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

The NM_004368.4(CNN2):​c.256G>A​(p.Glu86Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,461,084 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: not found (cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CNN2 NM_004368.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25

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, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNN2	NM_004368.4	c.256G>A	p.Glu86Lys	missense_variant	4/7	ENST00000263097.9	NP_004359.1
CNN2	NM_001303501.2	c.256G>A	p.Glu86Lys	missense_variant	4/7		NP_001290430.1
CNN2	NM_001303499.2	c.256G>A	p.Glu86Lys	missense_variant	4/7		NP_001290428.1
CNN2	NM_201277.3	c.256G>A	p.Glu86Lys	missense_variant	4/6		NP_958434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNN2	ENST00000263097.9	c.256G>A	p.Glu86Lys	missense_variant	4/7	1	NM_004368.4	ENSP00000263097.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461084 Hom.: 0 Cov.: 38 AF XY: 0.0000385 AC XY: 28 AN XY: 726754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.256G>A (p.E86K) alteration is located in exon 4 (coding exon 4) of the CNN2 gene. This alteration results from a G to A substitution at nucleotide position 256, causing the glutamic acid (E) at amino acid position 86 to be replaced by a lysine (K). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Pathogenic	3.2	M;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.2	D;.;D;D;D;.;.;.;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.016	D;.;D;D;D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;.;D;D;.;.;.;.
Vest4		0.99
MutPred		0.69		Gain of MoRF binding (P = 0.0011);.;Gain of MoRF binding (P = 0.0011);Gain of MoRF binding (P = 0.0011);Gain of MoRF binding (P = 0.0011);Gain of MoRF binding (P = 0.0011);.;.;.;
MVP		0.82
MPC		0.52
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.48
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2039516546; hg19: chr19-1032561;