Genetic Variant CLDND2:p.Ala136Pro (chr19-51367481-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152353.3(CLDND2):c.406G>C(p.Ala136Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CLDND2
NM_152353.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

Variant links:

Genes affected

CLDND2 (HGNC:28511): (claudin domain containing 2) Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CLDND2 links:

ENSG00000269403 (HGNC:):

ENSG00000269403 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDND2	NM_152353.3 link	c.406G>C	p.Ala136Pro	missense_variant	Exon 3 of 4	ENST00000291715.5	NP_689566.1	Q8NHS1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDND2	ENST00000291715.5 link	c.406G>C	p.Ala136Pro	missense_variant	Exon 3 of 4	1	NM_152353.3	ENSP00000291715.1	Q8NHS1
ENSG00000269403	ENST00000600067.1 link	n.115+405G>C		intron_variant	Intron 1 of 3	5		ENSP00000469452.1	M0QXX7
CLDND2	ENST00000601435.1 link	c.406G>C	p.Ala136Pro	missense_variant	Exon 4 of 5	3		ENSP00000472077.1	Q8NHS1
CLDND2	ENST00000593841.1 link	c.118+69G>C		intron_variant	Intron 2 of 2	5		ENSP00000471912.1	M0R1J6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000864

AC:

AN:

231562

Hom.:

AF XY:

0.00000801

AC XY:

AN XY:

124914

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000969

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450888

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720740

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000659

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406G>C (p.A136P) alteration is located in exon 3 (coding exon 3) of the CLDND2 gene. This alteration results from a G to C substitution at nucleotide position 406, causing the alanine (A) at amino acid position 136 to be replaced by a proline (P). 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

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.58

.;T

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.7

D;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0070

D;.

Sift4G

Uncertain

0.019

D;D

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.66

Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);

MVP

0.87

MPC

1.2

ClinPred

0.98

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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