Genetic Variant CLDN2:c.-178-3delT (chrX-106928040-AT-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_020384.4(CLDN2):c.-178-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 374,738 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000038 ( 0 hom. 3 hem. )

Consequence

CLDN2
NM_020384.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLDN2	NM_020384.4 link	c.-178-3delT	splice_region_variant, intron_variant	Intron 1 of 1	ENST00000336803.2	NP_065117.1	P57739
CLDN2	NM_001171092.1 link	c.-178-3delT	splice_region_variant, intron_variant	Intron 1 of 1		NP_001164563.1	P57739
CLDN2	NM_001171095.2 link	c.-178-3delT	splice_region_variant, intron_variant	Intron 1 of 1		NP_001164566.1	P57739

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDN2	ENST00000336803.2 link	c.-178-10delT	intron_variant	Intron 1 of 1	2	NM_020384.4	ENSP00000336571.1	P57739
CLDN2	ENST00000540876.1 link	c.-178-10delT	intron_variant	Intron 1 of 1	1		ENSP00000443230.1	P57739
CLDN2	ENST00000541806.6 link	c.-178-10delT	intron_variant	Intron 1 of 1	1		ENSP00000441283.1	P57739
MORC4	ENST00000604604.1 link	c.110+65189delA	intron_variant	Intron 1 of 1	2		ENSP00000474750.1	S4R3U3

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110809

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

33267

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:

0.0000378

Gnomad OTH

AF:

0.000674

GnomAD4 exome

AF:

0.0000379

AC:

AN:

263874

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

80682

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000864

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:

0.0000547

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110864

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33328

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:

0.0000378

Gnomad4 OTH

AF:

0.000666

Bravo

AF:

0.0000793

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over