NM_014343.3:c.565G>A

Variant names:

• chr7-101232620-C-T
• rs779074661
• NM_014343.3:c.565G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014343.3(CLDN15):​c.565G>A​(p.Glu189Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,589,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CLDN15 NM_014343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.638
• Publications: 0 publications found

Genes affected

CLDN15 (HGNC:2036): (claudin 15) 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. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0658997).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014343.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN15	NM_014343.3	MANE Select	c.565G>A	p.Glu189Lys	missense	Exon 4 of 5	NP_055158.1	P56746
	CLDN15	NM_001185080.2		c.565G>A	p.Glu189Lys	missense	Exon 5 of 6	NP_001172009.1	P56746

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN15	ENST00000308344.10	TSL:1 MANE Select	c.565G>A	p.Glu189Lys	missense	Exon 4 of 5	ENSP00000308870.5	P56746
	CLDN15	ENST00000401528.5	TSL:2	c.565G>A	p.Glu189Lys	missense	Exon 5 of 6	ENSP00000385300.1	P56746
	CLDN15	ENST00000412417.1	TSL:5	c.496G>A	p.Glu166Lys	missense	Exon 4 of 4	ENSP00000390230.1	C9JHQ4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152182 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000101 AC: 2 AN: 197164 AF XY: 0.0000185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000238

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000244 AC: 35 AN: 1436972 Hom.: 0 Cov.: 32 AF XY: 0.0000252 AC XY: 18 AN XY: 713052

African (AFR) AF: 0.00 AC: 0 AN: 33068

American (AMR) AF: 0.00 AC: 0 AN: 39890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25524

East Asian (EAS) AF: 0.00 AC: 0 AN: 38708

South Asian (SAS) AF: 0.00 AC: 0 AN: 83888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.0000309 AC: 34 AN: 1100176

Other (OTH) AF: 0.0000169 AC: 1 AN: 59324

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000566 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000841 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.64
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.14
Sift	Benign	0.85	T
Sift4G	Benign	0.92	T
Polyphen		0.0080	B
Vest4		0.22
MutPred		0.39		Gain of methylation at E189 (P = 0.0095)
MVP		0.75
MPC		0.36
ClinPred		0.071	T
GERP RS		1.6
Varity_R		0.064
gMVP		0.32
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs779074661; hg19: chr7-100875901;