chrX-106928296-T-C

Position:

• chrX-106928296-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020384.4(CLDN2):​c.68T>C​(p.Val23Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CLDN2 NM_020384.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2759008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN2	NM_020384.4	c.68T>C	p.Val23Ala	missense_variant	2/2	ENST00000336803.2	NP_065117.1
CLDN2	NM_001171092.1	c.68T>C	p.Val23Ala	missense_variant	2/2		NP_001164563.1
CLDN2	NM_001171095.2	c.68T>C	p.Val23Ala	missense_variant	2/2		NP_001164566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN2	ENST00000336803.2	c.68T>C	p.Val23Ala	missense_variant	2/2	2	NM_020384.4	ENSP00000336571.1
CLDN2	ENST00000540876.1	c.68T>C	p.Val23Ala	missense_variant	2/2	1		ENSP00000443230.1
CLDN2	ENST00000541806.6	c.68T>C	p.Val23Ala	missense_variant	2/2	1		ENSP00000441283.1
MORC4	ENST00000604604.1	c.110+64934A>G		intron_variant		2		ENSP00000474750.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.68T>C (p.V23A) alteration is located in exon 2 (coding exon 1) of the CLDN2 gene. This alteration results from a T to C substitution at nucleotide position 68, causing the valine (V) at amino acid position 23 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;D
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.52	T;.;.
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.89	L;L;L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.0040	B;B;B
Vest4		0.12
MutPred		0.65		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.89
MPC		1.1
ClinPred		0.41	T
GERP RS		4.4
Varity_R		0.20
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-106171526;