Genetic Variant CNN2:p.Ala126Ser (chr19-1032682-G-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.376G>T(p.Ala126Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000096 in 1,458,332 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CNN2
NM_004368.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.25

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:

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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.376G>T	p.Ala126Ser	missense_variant	Exon 4 of 7	ENST00000263097.9	NP_004359.1	Q99439-1
CNN2	NM_001303501.2 link	c.376G>T	p.Ala126Ser	missense_variant	Exon 4 of 7		NP_001290430.1	Q99439B4DUT8
CNN2	NM_201277.3 link	c.376G>T	p.Ala126Ser	missense_variant	Exon 4 of 6		NP_958434.1	Q99439-2
CNN2	NM_001303499.2 link	c.357+19G>T		intron_variant	Intron 4 of 6		NP_001290428.1	Q99439B4DDF4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNN2	ENST00000263097.9 link	c.376G>T	p.Ala126Ser	missense_variant	Exon 4 of 7	1	NM_004368.4	ENSP00000263097.2		Q99439-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

246850

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134098

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000960

AC:

AN:

1458332

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725332

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376G>T (p.A126S) alteration is located in exon 4 (coding exon 4) of the CNN2 gene. This alteration results from a G to T substitution at nucleotide position 376, causing the alanine (A) at amino acid position 126 to be replaced by a serine (S). 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

0.16

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;.;.;D;.;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;.

M_CAP

Pathogenic

0.58

MetaRNN

Uncertain

0.70

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.8

L;.;L;.;.;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.1

N;.;N;N;.;.;N

REVEL

Uncertain

0.61

Sift

Benign

0.11

T;.;T;T;.;.;T

Sift4G

Benign

0.17

T;T;T;T;T;T;T

Polyphen

0.36

B;.;.;B;.;.;.

Vest4

0.80

MutPred

0.65

Loss of loop (P = 0.0073);.;Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);.;.;.;

MVP

0.95

MPC

0.34

ClinPred

0.58

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.16

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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