X-106928040-AT-ATT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 4P and 10B. PVS1_Strong BP6_Moderate BA1

The NM_020384.4(CLDN2):​c.-178-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 374,752 control chromosomes in the GnomAD database, including 71 homozygotes. There are 1,365 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (55 hom., 727 hem., cov: 22)
  • Exomes 𝑓: 0.0093 (16 hom. 638 hem.)
• Consequence: CLDN2 NM_020384.4 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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_benign. 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 9.4, offset of 0 (no position change), new splice context is: gtttatggatttttttttAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant X-106928040-A-AT is Benign according to our data. Variant chrX-106928040-A-AT is described in ClinVar as Benign. ClinVar VariationId is 1275359.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

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.-178-3dupT		splice_acceptor intron	N/A	NP_065117.1	P57739
	CLDN2	NM_001171092.1		c.-178-3dupT		splice_acceptor intron	N/A	NP_001164563.1	P57739
	CLDN2	NM_001171095.2		c.-178-3dupT		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_-178-10insT		intron	N/A	ENSP00000336571.1	P57739
	CLDN2	ENST00000540876.1	TSL:1	c.-178-11_-178-10insT		intron	N/A	ENSP00000443230.1	P57739
	CLDN2	ENST00000541806.6	TSL:1	c.-178-11_-178-10insT		intron	N/A	ENSP00000441283.1	P57739

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 2707 AN: 110807 Hom.: 53 Cov.: 22

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00114

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0236

GnomAD4 exome AF: 0.00928 AC: 2448 AN: 263890 Hom.: 16 Cov.: 3 AF XY: 0.00791 AC XY: 638 AN XY: 80696

African (AFR) AF: 0.0625 AC: 548 AN: 8773

American (AMR) AF: 0.00821 AC: 95 AN: 11571

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 1 AN: 8459

East Asian (EAS) AF: 0.000595 AC: 13 AN: 21848

South Asian (SAS) AF: 0.00112 AC: 12 AN: 10745

European-Finnish (FIN) AF: 0.00297 AC: 59 AN: 19866

Middle Eastern (MID) AF: 0.00341 AC: 4 AN: 1174

European-Non Finnish (NFE) AF: 0.00908 AC: 1495 AN: 164649

Other (OTH) AF: 0.0132 AC: 221 AN: 16805

GnomAD4 genome AF: 0.0244 AC: 2710 AN: 110862 Hom.: 55 Cov.: 22 AF XY: 0.0218 AC XY: 727 AN XY: 33324

African (AFR) AF: 0.0657 AC: 2000 AN: 30439

American (AMR) AF: 0.0115 AC: 120 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: 0.00114 AC: 3 AN: 2630

European-Finnish (FIN) AF: 0.00235 AC: 14 AN: 5947

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

European-Non Finnish (NFE) AF: 0.0102 AC: 538 AN: 52883

Other (OTH) AF: 0.0233 AC: 35 AN: 1502

Alfa AF: 0.00305 Hom.: 18

Bravo AF: 0.0285

Asia WGS AF: 0.00318 AC: 8 AN: 2522

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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;