Variant 19-1036202-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004368.4(CNN2):c.463G>A(p.Asp155Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,557,538 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000063 ( 2 hom. )

Consequence

CNN2
NM_004368.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.74

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06736404).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNN2	NM_004368.4 linkuse as main transcript	c.463G>A	p.Asp155Asn	missense_variant	5/7	ENST00000263097.9	NP_004359.1	Q99439-1
CNN2	NM_001303501.2 linkuse as main transcript	c.526G>A	p.Asp176Asn	missense_variant	5/7		NP_001290430.1	Q99439B4DUT8
CNN2	NM_001303499.2 linkuse as main transcript	c.430G>A	p.Asp144Asn	missense_variant	5/7		NP_001290428.1	Q99439B4DDF4
CNN2	NM_201277.3 linkuse as main transcript	c.391-214G>A		intron_variant			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.463G>A	p.Asp155Asn	missense_variant	5/7	1	NM_004368.4	ENSP00000263097.2		Q99439-1

Frequencies

GnomAD3 genomes

AF:

0.000146

AC:

AN:

150526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00127

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000488

GnomAD3 exomes

AF:

0.000147

AC:

AN:

244632

Hom.:

AF XY:

0.000189

AC XY:

AN XY:

132208

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.000815

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.0000633

AC:

AN:

1406898

Hom.:

Cov.:

AF XY:

0.0000906

AC XY:

AN XY:

695222

show subpopulations

Gnomad4 AFR exome

AF:

0.000287

Gnomad4 AMR exome

AF:

0.0000882

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000769

Gnomad4 SAS exome

AF:

0.000742

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000735

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.000146

AC:

AN:

150640

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73546

show subpopulations

Gnomad4 AFR

AF:

0.000292

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00127

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000483

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.00115

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.463G>A (p.D155N) alteration is located in exon 5 (coding exon 5) of the CNN2 gene. This alteration results from a G to A substitution at nucleotide position 463, causing the aspartic acid (D) at amino acid position 155 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;.;T;.;.;.

Eigen

Benign

0.19

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.71

T;T;T;T;T;.

M_CAP

Benign

0.064

MetaRNN

Benign

0.067

T;T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.6

L;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.2

N;N;N;.;.;D

REVEL

Benign

0.20

Sift

Benign

0.14

T;T;T;.;.;T

Sift4G

Benign

0.13

T;T;T;T;T;T

Polyphen

0.99

D;P;D;.;.;.

Vest4

0.88

MVP

0.72

MPC

0.098

ClinPred

0.12

GERP RS

3.7

Varity_R

0.19

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