Variant 19-1037896-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004368.4(CNN2):c.926A>G(p.Tyr309Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,574,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 38)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

CNN2
NM_004368.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

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:

CNN2 (HGNC:):

CNN2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.092549145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNN2	NM_004368.4 linkuse as main transcript	c.926A>G	p.Tyr309Cys	missense_variant	7/7	ENST00000263097.9	NP_004359.1	Q99439-1
CNN2	NM_001303501.2 linkuse as main transcript	c.989A>G	p.Tyr330Cys	missense_variant	7/7		NP_001290430.1	Q99439B4DUT8
CNN2	NM_001303499.2 linkuse as main transcript	c.893A>G	p.Tyr298Cys	missense_variant	7/7		NP_001290428.1	Q99439B4DDF4
CNN2	NM_201277.3 linkuse as main transcript	c.809A>G	p.Tyr270Cys	missense_variant	6/6		NP_958434.1	Q99439-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNN2	ENST00000263097.9 linkuse as main transcript	c.926A>G	p.Tyr309Cys	missense_variant	7/7	1	NM_004368.4	ENSP00000263097.2		Q99439-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000188

AC:

AN:

222836

Hom.:

AF XY:

0.000188

AC XY:

AN XY:

122474

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000335

Gnomad ASJ exome

AF:

0.000130

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000386

Gnomad OTH exome

AF:

0.000189

GnomAD4 exome

AF:

0.000259

AC:

369

AN:

1422566

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

185

AN XY:

702484

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.0000733

Gnomad4 ASJ exome

AF:

0.000328

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000319

Gnomad4 OTH exome

AF:

0.000171

GnomAD4 genome

AF:

0.000105

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000202

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000248

AC:

ExAC

AF:

0.000234

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.926A>G (p.Y309C) alteration is located in exon 7 (coding exon 7) of the CNN2 gene. This alteration results from a A to G substitution at nucleotide position 926, causing the tyrosine (Y) at amino acid position 309 to be replaced by a cysteine (C). 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

0.090

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.52

D;.;.;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.050

MetaRNN

Benign

0.093

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;.;.;.

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.7

D;N;D;D

REVEL

Benign

0.14

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.015

B;.;B;B

Vest4

0.24

MVP

0.19

MPC

0.12

ClinPred

0.16

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.34

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