chr17-7260724-G-A

Position:

• chr17-7260724-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001307.6(CLDN7):​c.391C>T​(p.Leu131Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN7 NM_001307.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

Genes affected

CLDN7 (HGNC:2049): (claudin 7) This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. Differential expression of this gene has been observed in different types of malignancies, including breast cancer, ovarian cancer, hepatocellular carcinomas, urinary tumors, prostate cancer, lung cancer, head and neck cancers, thyroid carcinomas, etc.. Alternatively spliced transcript variants encoding different isoforms have been found.[provided by RefSeq, May 2010]

ENSG00000262302 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN7	NM_001307.6	c.391C>T	p.Leu131Phe	missense_variant, splice_region_variant	3/4	ENST00000360325.11	NP_001298.3
CLDN7	NM_001185022.2	c.391C>T	p.Leu131Phe	missense_variant, splice_region_variant	4/5		NP_001171951.1
CLDN7	NM_001185023.2	c.388+97C>T		intron_variant			NP_001171952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN7	ENST00000360325.11	c.391C>T	p.Leu131Phe	missense_variant, splice_region_variant	3/4	1	NM_001307.6	ENSP00000353475.7
ENSG00000262302	ENST00000577138.1	n.223+1097C>T		intron_variant		3		ENSP00000460571.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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 Cov.: 33

GnomAD4 genome Cov.: 33

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

Feb 21, 2024

The c.391C>T (p.L131F) alteration is located in exon 3 (coding exon 3) of the CLDN7 gene. This alteration results from a C to T substitution at nucleotide position 391, causing the leucine (L) at amino acid position 131 to be replaced by a phenylalanine (F). 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	0.18
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D;D;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.024	D;D;.;.
Sift4G	Benign	0.086	T;T;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.32
MutPred		0.67		Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;.;
MVP		0.96
MPC		0.77
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.56
gMVP		0.72

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: rs1256012497; hg19: chr17-7164043;