17-7260892-C-A

Position:

• chr17-7260892-C-A

Variant summary

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

The NM_001307.6(CLDN7):​c.317G>T​(p.Arg106Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CLDN7 NM_001307.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.442

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3847314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN7	NM_001307.6	c.317G>T	p.Arg106Leu	missense_variant	2/4	ENST00000360325.11	NP_001298.3
CLDN7	NM_001185022.2	c.317G>T	p.Arg106Leu	missense_variant	3/5		NP_001171951.1
CLDN7	NM_001185023.2	c.317G>T	p.Arg106Leu	missense_variant	2/3		NP_001171952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN7	ENST00000360325.11	c.317G>T	p.Arg106Leu	missense_variant	2/4	1	NM_001307.6	ENSP00000353475.7
ENSG00000262302	ENST00000577138.1	n.223+929G>T		intron_variant		3		ENSP00000460571.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461866 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727240

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

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

May 04, 2022

The c.317G>T (p.R106L) alteration is located in exon 2 (coding exon 2) of the CLDN7 gene. This alteration results from a G to T substitution at nucleotide position 317, causing the arginine (R) at amino acid position 106 to be replaced by a leucine (L). 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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;D;D;.;D;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.92	.;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Uncertain	2.5	M;.;M;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D;D;D;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.025	D;D;D;.;.;.
Sift4G	Benign	0.13	T;D;T;.;.;.
Polyphen		0.058	B;B;B;.;.;.
Vest4		0.20
MutPred		0.62		Loss of MoRF binding (P = 0.0385);Loss of MoRF binding (P = 0.0385);Loss of MoRF binding (P = 0.0385);.;.;Loss of MoRF binding (P = 0.0385);
MVP		0.89
MPC		0.58
ClinPred		0.95	D
GERP RS		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.65

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: rs761455420; hg19: chr17-7164211;