X-106928690-C-G

Position:

• chrX-106928690-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020384.4(CLDN2):​c.462C>G​(p.Asp154Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,687 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CLDN2 NM_020384.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.782

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10283601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN2	NM_020384.4	c.462C>G	p.Asp154Glu	missense_variant	2/2	ENST00000336803.2	NP_065117.1
CLDN2	NM_001171092.1	c.462C>G	p.Asp154Glu	missense_variant	2/2		NP_001164563.1
CLDN2	NM_001171095.2	c.462C>G	p.Asp154Glu	missense_variant	2/2		NP_001164566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN2	ENST00000336803.2	c.462C>G	p.Asp154Glu	missense_variant	2/2	2	NM_020384.4	ENSP00000336571	P1
CLDN2	ENST00000540876.1	c.462C>G	p.Asp154Glu	missense_variant	2/2	1		ENSP00000443230	P1
CLDN2	ENST00000541806.6	c.462C>G	p.Asp154Glu	missense_variant	2/2	1		ENSP00000441283	P1
MORC4	ENST00000604604.1	c.111+64540G>C		intron_variant		2		ENSP00000474750

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097687 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363051

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

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

Mar 30, 2024

The c.462C>G (p.D154E) alteration is located in exon 2 (coding exon 1) of the CLDN2 gene. This alteration results from a C to G substitution at nucleotide position 462, causing the aspartic acid (D) at amino acid position 154 to be replaced by a glutamic acid (E). 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	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T;T;T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.61	T;.;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.38	N;N;N
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.46	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.46	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.018	B;B;B
Vest4		0.069
MutPred		0.20		Loss of ubiquitination at K157 (P = 0.1113);Loss of ubiquitination at K157 (P = 0.1113);Loss of ubiquitination at K157 (P = 0.1113);
MVP		0.54
MPC		0.51
ClinPred		0.13	T
GERP RS		2.3
Varity_R		0.074
gMVP		0.49

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

Other links and lift over

dbSNP: rs140513089; hg19: chrX-106171920;