Genetic Variant CNN2:p.Asp156Tyr (chr19-1036205-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_004368.4(CNN2):c.466G>T(p.Asp156Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D156N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CNN2
NM_004368.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.61

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.15171 (below the threshold of 3.09). Trascript score misZ: 0.22112 (below the threshold of 3.09).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004368.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNN2	NM_004368.4	MANE Select	c.466G>T	p.Asp156Tyr	missense	Exon 5 of 7	NP_004359.1	Q99439-1
CNN2	NM_001303501.2		c.529G>T	p.Asp177Tyr	missense	Exon 5 of 7	NP_001290430.1	B4DUT8
CNN2	NM_001303499.2		c.433G>T	p.Asp145Tyr	missense	Exon 5 of 7	NP_001290428.1	B4DDF4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNN2	ENST00000263097.9	TSL:1 MANE Select	c.466G>T	p.Asp156Tyr	missense	Exon 5 of 7	ENSP00000263097.2	Q99439-1
CNN2	ENST00000607102.1	TSL:1	c.34-211G>T		intron	N/A	ENSP00000475175.1	U3KPS3
CNN2	ENST00000562958.6	TSL:2	c.529G>T	p.Asp177Tyr	missense	Exon 5 of 7	ENSP00000456436.1	B4DUT8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1417084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700668

African (AFR)

AF:

0.00

AC:

AN:

31894

American (AMR)

AF:

0.00

AC:

AN:

37560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23432

East Asian (EAS)

AF:

0.00

AC:

AN:

38976

South Asian (SAS)

AF:

0.00

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5032

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090938

Other (OTH)

AF:

0.00

AC:

AN:

58358

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Benign

0.86

DEOGEN2

Uncertain

0.60

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.077

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.73

MutationAssessor

Benign

2.0

PhyloP100

9.6

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.31

Sift

Benign

0.094

Sift4G

Uncertain

0.021

Polyphen

0.038

Vest4

0.56

MutPred

0.46

Gain of phosphorylation at D177 (P = 0.0276)

MVP

0.73

MPC

0.13

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.64

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over