Genetic Variant NM_020384.4:c.265G>A (chrX-106928493-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020384.4(CLDN2):c.265G>A(p.Ala89Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,222 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

CLDN2
NM_020384.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.61

Variant links:

Genes affected

CLDN2 (HGNC:2041): (claudin 2) This gene product belongs to the claudin protein family whose members have been identified as major integral membrane proteins localized exclusively at tight junctions. Claudins are expressed in an organ-specific manner and regulate tissue-specific physiologic properties of tight junctions. This protein is expressed in the intestine. Alternatively spliced transcript variants with different 5' untranslated region have been found for this gene.[provided by RefSeq, Jan 2010]

CLDN2 links:

MORC4 (HGNC:23485): (MORC family CW-type zinc finger 4) In human, the four current members of the microrchidia (morc) gene family share an N-terminal ATPase-like ATP-binding region and a CW four-cysteine zinc-finger motif. The protein encoded by this gene also has a nuclear matrix binding domain and a two-stranded coiled-coil motif near its C-terminus. This gene is widely expressed at low levels in normal tissues and has elevated expression in placenta and testis. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

MORC4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23800337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN2	NM_020384.4 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 2 of 2	ENST00000336803.2	NP_065117.1	P57739
CLDN2	NM_001171092.1 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 2 of 2		NP_001164563.1	P57739
CLDN2	NM_001171095.2 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 2 of 2		NP_001164566.1	P57739

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDN2	ENST00000336803.2 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 2 of 2	2	NM_020384.4	ENSP00000336571.1	P57739
CLDN2	ENST00000540876.1 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 2 of 2	1		ENSP00000443230.1	P57739
CLDN2	ENST00000541806.6 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 2 of 2	1		ENSP00000441283.1	P57739
MORC4	ENST00000604604.1 link	c.110+64737C>T		intron_variant	Intron 1 of 1	2		ENSP00000474750.1	S4R3U3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098222

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363576

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265G>A (p.A89T) alteration is located in exon 2 (coding exon 1) of the CLDN2 gene. This alteration results from a G to A substitution at nucleotide position 265, causing the alanine (A) at amino acid position 89 to be replaced by a threonine (T). 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

0.094

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

T;T;T

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

T;.;.

M_CAP

Benign

0.058

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Uncertain

0.012

MutationAssessor

Benign

2.0

M;M;M

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.52

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.032

D;D;D

Sift4G

Benign

0.068

T;T;T

Polyphen

0.035

B;B;B

Vest4

0.14

MutPred

0.54

Gain of glycosylation at A89 (P = 0.0308);Gain of glycosylation at A89 (P = 0.0308);Gain of glycosylation at A89 (P = 0.0308);

MVP

0.87

MPC

0.53

ClinPred

0.62

GERP RS

3.6

Varity_R

0.15

gMVP

0.82

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over