X-106928040-A-AT

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PVS1_StrongBP6_ModerateBA1

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

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLDN2	NM_020384.4 link	c.-178-3dupT	splice_acceptor_variant, intron_variant	Intron 1 of 1	ENST00000336803.2	NP_065117.1	P57739
CLDN2	NM_001171092.1 link	c.-178-3dupT	splice_acceptor_variant, intron_variant	Intron 1 of 1		NP_001164563.1	P57739
CLDN2	NM_001171095.2 link	c.-178-3dupT	splice_acceptor_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.-178-11_-178-10insT	intron_variant	Intron 1 of 1	2	NM_020384.4	ENSP00000336571.1	P57739
CLDN2	ENST00000540876.1 link	c.-178-11_-178-10insT	intron_variant	Intron 1 of 1	1		ENSP00000443230.1	P57739
CLDN2	ENST00000541806.6 link	c.-178-11_-178-10insT	intron_variant	Intron 1 of 1	1		ENSP00000441283.1	P57739
MORC4	ENST00000604604.1 link	c.110+65189_110+65190insA	intron_variant	Intron 1 of 1	2		ENSP00000474750.1	S4R3U3

Frequencies

GnomAD3 genomes

AF:

0.0244

AC:

2707

AN:

110807

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

725

AN XY:

33263

show subpopulations

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.:

Cov.:

AF XY:

0.00791

AC XY:

638

AN XY:

80696

show subpopulations

Gnomad4 AFR exome

AF:

0.0625

Gnomad4 AMR exome

AF:

0.00821

Gnomad4 ASJ exome

AF:

0.000118

Gnomad4 EAS exome

AF:

0.000595

Gnomad4 SAS exome

AF:

0.00112

Gnomad4 FIN exome

AF:

0.00297

Gnomad4 NFE exome

AF:

0.00908

Gnomad4 OTH exome

AF:

0.0132

GnomAD4 genome

AF:

0.0244

AC:

2710

AN:

110862

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

727

AN XY:

33324

show subpopulations

Gnomad4 AFR

AF:

0.0657

Gnomad4 AMR

AF:

0.0115

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00114

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.0102

Gnomad4 OTH

AF:

0.0233

Bravo

AF:

0.0285

Asia WGS

AF:

0.00318

AC:

AN:

2522

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over