X-106928040-AT-A

Variant names:

• chrX-106928040-AT-A
• rs202232558
• NM_020384.4:c.-178-3delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.-178-3delT		splice_region intron	N/A	NP_065117.1	P57739
	CLDN2	NM_001171092.1		c.-178-3delT		splice_region intron	N/A	NP_001164563.1	P57739
	CLDN2	NM_001171095.2		c.-178-3delT		splice_region 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.-178-10delT		intron	N/A	ENSP00000336571.1	P57739
	CLDN2	ENST00000540876.1	TSL:1	c.-178-10delT		intron	N/A	ENSP00000443230.1	P57739
	CLDN2	ENST00000541806.6	TSL:1	c.-178-10delT		intron	N/A	ENSP00000441283.1	P57739

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110809 Hom.: 0 Cov.: 22

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: 10 AN: 263874 Hom.: 0 Cov.: 3 AF XY: 0.0000372 AC XY: 3 AN XY: 80682

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.0000864 AC: 1 AN: 11571

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 21842

South Asian (SAS) AF: 0.00 AC: 0 AN: 10746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19861

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

European-Non Finnish (NFE) AF: 0.0000547 AC: 9 AN: 164642

Other (OTH) AF: 0.00 AC: 0 AN: 16801

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00353511), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000271 AC: 3 AN: 110864 Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1 AN XY: 33328

African (AFR) AF: 0.00 AC: 0 AN: 30442

American (AMR) AF: 0.00 AC: 0 AN: 10464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2629

East Asian (EAS) AF: 0.00 AC: 0 AN: 3479

South Asian (SAS) AF: 0.00 AC: 0 AN: 2628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5947

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52884

Other (OTH) AF: 0.000666 AC: 1 AN: 1502

Alfa AF: 0.00 Hom.: 18

Bravo AF: 0.0000793

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

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

Other links and lift over

dbSNP: rs202232558; hg19: chrX-106171270; COSMIC: COSV61020720;