Genetic Variant CNN2:p.Thr287Ile (chr19-1037830-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_Strong

The NM_004368.4(CNN2):c.860C>T(p.Thr287Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,607,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. T287S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 38)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CNN2
NM_004368.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.288

Publications

1 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: Likely_benign. The variant received -3 ACMG points.

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).

BP4

Computational evidence support a benign effect (MetaRNN=0.03516215).

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.860C>T	p.Thr287Ile	missense	Exon 7 of 7	NP_004359.1	Q99439-1
CNN2	NM_001303501.2		c.923C>T	p.Thr308Ile	missense	Exon 7 of 7	NP_001290430.1	B4DUT8
CNN2	NM_001303499.2		c.827C>T	p.Thr276Ile	missense	Exon 7 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.860C>T	p.Thr287Ile	missense	Exon 7 of 7	ENSP00000263097.2	Q99439-1
CNN2	ENST00000562958.6	TSL:2	c.923C>T	p.Thr308Ile	missense	Exon 7 of 7	ENSP00000456436.1	B4DUT8
CNN2	ENST00000926772.1		c.854C>T	p.Thr285Ile	missense	Exon 7 of 7	ENSP00000596831.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000203

AC:

AN:

246026

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000276

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455390

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.000101

AC:

AN:

39576

South Asian (SAS)

AF:

0.00

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4182

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109000

Other (OTH)

AF:

0.00

AC:

AN:

60018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152392

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41596

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000248

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.21

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.093

M_CAP

Benign

0.033

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-0.29

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.1

REVEL

Benign

0.064

Sift

Benign

0.030

Sift4G

Benign

0.23

Polyphen

0.089

Vest4

0.043

MutPred

0.18

Loss of glycosylation at T308 (P = 0.0028)

MVP

0.24

MPC

0.11

ClinPred

0.033

GERP RS

-0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.32

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over