X-106928701-T-A

Position:

chrX-106928701-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_020384.4(CLDN2):c.473T>A(p.Phe158Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,209,703 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 132 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., 60 hem., cov: 22)

Exomes 𝑓: 0.00023 ( 0 hom. 72 hem. )

Consequence

CLDN2
NM_020384.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0460

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0113886).

BP6

Variant X-106928701-T-A is Benign according to our data. Variant chrX-106928701-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 777817.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 60 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CLDN2	NM_020384.4 linkuse as main transcript	c.473T>A	p.Phe158Tyr	missense_variant	2/2	ENST00000336803.2
CLDN2	NM_001171092.1 linkuse as main transcript	c.473T>A	p.Phe158Tyr	missense_variant	2/2
CLDN2	NM_001171095.2 linkuse as main transcript	c.473T>A	p.Phe158Tyr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CLDN2	ENST00000336803.2 linkuse as main transcript	c.473T>A	p.Phe158Tyr	missense_variant	2/2	2	NM_020384.4	P1
CLDN2	ENST00000540876.1 linkuse as main transcript	c.473T>A	p.Phe158Tyr	missense_variant	2/2	1		P1
CLDN2	ENST00000541806.6 linkuse as main transcript	c.473T>A	p.Phe158Tyr	missense_variant	2/2	1		P1
MORC4	ENST00000604604.1 linkuse as main transcript	c.111+64529A>T		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

238

AN:

111728

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

AN XY:

33880

show subpopulations

Gnomad AFR

AF:

0.00733

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000854

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:

0.0000376

Gnomad OTH

AF:

0.00133

GnomAD3 exomes

AF:

0.000589

AC:

108

AN:

183406

Hom.:

AF XY:

0.000457

AC XY:

AN XY:

67840

show subpopulations

Gnomad AFR exome

AF:

0.00737

Gnomad AMR exome

AF:

0.000401

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000231

AC:

254

AN:

1097921

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

AN XY:

363275

show subpopulations

Gnomad4 AFR exome

AF:

0.00765

Gnomad4 AMR exome

AF:

0.000511

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000131

Gnomad4 OTH exome

AF:

0.000477

GnomAD4 genome

AF:

0.00213

AC:

238

AN:

111782

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

AN XY:

33944

show subpopulations

Gnomad4 AFR

AF:

0.00731

Gnomad4 AMR

AF:

0.000853

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.000271

Hom.:

Bravo

AF:

0.00238

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000692

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

9.6

DANN

Benign

0.83

DEOGEN2

Benign

0.32

T;T;T

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.70

T;.;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.64

N;N;N

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.87

N;N;N

REVEL

Benign

0.29

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.68

T;T;T

Polyphen

0.0060

B;B;B

Vest4

0.22

MVP

0.85

MPC

0.63

ClinPred

0.0078

GERP RS

2.6

Varity_R

0.14

gMVP

0.77

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