Genetic Variant CNN2:p.Arg227Trp (chr19-1037649-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004368.4(CNN2):c.679C>T(p.Arg227Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,611,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 37)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CNN2
NM_004368.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

Variant links:

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]

CNN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNN2	NM_004368.4 link	c.679C>T	p.Arg227Trp	missense_variant	Exon 7 of 7	ENST00000263097.9	NP_004359.1	Q99439-1
CNN2	NM_001303501.2 link	c.742C>T	p.Arg248Trp	missense_variant	Exon 7 of 7		NP_001290430.1	Q99439B4DUT8
CNN2	NM_001303499.2 link	c.646C>T	p.Arg216Trp	missense_variant	Exon 7 of 7		NP_001290428.1	Q99439B4DDF4
CNN2	NM_201277.3 link	c.562C>T	p.Arg188Trp	missense_variant	Exon 6 of 6		NP_958434.1	Q99439-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNN2	ENST00000263097.9 link	c.679C>T	p.Arg227Trp	missense_variant	Exon 7 of 7	1	NM_004368.4	ENSP00000263097.2		Q99439-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

245984

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134422

show subpopulations

Gnomad AFR exome

AF:

0.000135

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:

0.0000362

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1458800

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725690

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000403

Hom.:

ExAC

AF:

0.0000497

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.679C>T (p.R227W) alteration is located in exon 7 (coding exon 7) of the CNN2 gene. This alteration results from a C to T substitution at nucleotide position 679, causing the arginine (R) at amino acid position 227 to be replaced by a tryptophan (W). 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

0.93

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.;.;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.84

T;T;T;D;T

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.44

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.7

L;.;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.5

D;D;D;D;.

REVEL

Benign

0.20

Sift

Uncertain

0.0010

D;D;D;D;.

Sift4G

Benign

0.073

T;T;T;T;T

Polyphen

0.51

P;.;P;B;.

Vest4

0.82

MVP

0.63

MPC

0.10

ClinPred

0.64

GERP RS

1.9

Varity_R

0.58

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over