X-106928257-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_020384.4(CLDN2):c.29G>C(p.Gly10Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000207 in 1,209,829 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 6 hem. )

Consequence

CLDN2
NM_020384.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.69

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 Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN2	NM_020384.4 link	c.29G>C	p.Gly10Ala	missense_variant	Exon 2 of 2	ENST00000336803.2	NP_065117.1	P57739
CLDN2	NM_001171092.1 link	c.29G>C	p.Gly10Ala	missense_variant	Exon 2 of 2		NP_001164563.1	P57739
CLDN2	NM_001171095.2 link	c.29G>C	p.Gly10Ala	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.29G>C	p.Gly10Ala	missense_variant	Exon 2 of 2	2	NM_020384.4	ENSP00000336571.1	P57739
CLDN2	ENST00000540876.1 link	c.29G>C	p.Gly10Ala	missense_variant	Exon 2 of 2	1		ENSP00000443230.1	P57739
CLDN2	ENST00000541806.6 link	c.29G>C	p.Gly10Ala	missense_variant	Exon 2 of 2	1		ENSP00000441283.1	P57739
MORC4	ENST00000604604.1 link	c.110+64973C>G		intron_variant	Intron 1 of 1	2		ENSP00000474750.1	S4R3U3

Frequencies

GnomAD3 genomes

AF:

0.0000534

AC:

AN:

112418

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34566

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000275

AC:

AN:

181751

Hom.:

AF XY:

0.0000302

AC XY:

AN XY:

66285

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.0000493

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1097411

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

362811

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.0000214

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000534

AC:

AN:

112418

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34566

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29G>C (p.G10A) alteration is located in exon 2 (coding exon 1) of the CLDN2 gene. This alteration results from a G to C substitution at nucleotide position 29, causing the glycine (G) at amino acid position 10 to be replaced by an alanine (A). 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

0.22

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;D;D

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

T;.;.

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0090

D;D;D

Sift4G

Benign

0.12

T;T;T

Polyphen

0.0060

B;B;B

Vest4

0.47

MutPred

0.80

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.85

MPC

1.0

ClinPred

0.27

GERP RS

4.7

Varity_R

0.77

gMVP

0.98

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

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