chrX-106928040-A-ATT

Variant names:

• chrX-106928040-A-ATT
• rs202232558
• NM_020384.4:c.-178-4_-178-3dupTT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_020384.4(CLDN2):​c.-178-4_-178-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000379 in 263,929 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000038 (0 hom. 0 hem.)
• Consequence: CLDN2 NM_020384.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 4.0562773 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.6, offset of 0 (no position change), new splice context is: tttatggattttttttttAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020384.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN2	NM_020384.4	MANE Select	c.-178-4_-178-3dupTT		splice_acceptor intron	N/A	NP_065117.1	P57739
	CLDN2	NM_001171092.1		c.-178-4_-178-3dupTT		splice_acceptor intron	N/A	NP_001164563.1	P57739
	CLDN2	NM_001171095.2		c.-178-4_-178-3dupTT		splice_acceptor intron	N/A	NP_001164566.1	P57739

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN2	ENST00000336803.2	TSL:2 MANE Select	c.-178-11_-178-10insTT		intron	N/A	ENSP00000336571.1	P57739
	CLDN2	ENST00000540876.1	TSL:1	c.-178-11_-178-10insTT		intron	N/A	ENSP00000443230.1	P57739
	CLDN2	ENST00000541806.6	TSL:1	c.-178-11_-178-10insTT		intron	N/A	ENSP00000441283.1	P57739

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000379 AC: 1 AN: 263929 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 80723

African (AFR) AF: 0.00 AC: 0 AN: 8777

American (AMR) AF: 0.00 AC: 0 AN: 11573

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8459

East Asian (EAS) AF: 0.00 AC: 0 AN: 21853

South Asian (SAS) AF: 0.00 AC: 0 AN: 10748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19867

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1175

European-Non Finnish (NFE) AF: 0.00000607 AC: 1 AN: 164672

Other (OTH) AF: 0.00 AC: 0 AN: 16805

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202232558; hg19: chrX-106171270;