21-36461191-T-C

Variant names:

• chr21-36461191-T-C
• rs1555841637
• NM_001146079.2:c.505A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001146079.2(CLDN14):​c.505A>G​(p.Ile169Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CLDN14 NM_001146079.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.09
• Publications: 0 publications found

Genes affected

CLDN14 (HGNC:2035): (claudin 14) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. The encoded protein also binds specifically to the WW domain of Yes-associated protein. Defects in this gene are the cause of an autosomal recessive form of nonsyndromic sensorineural deafness. It is also reported that four synonymous variants in this gene are associated with kidney stones and reduced bone mineral density. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2010]

LNCTSI (HGNC:56660): (lncRNA TGF-beta/SMAD3 pathway interacting)

CLDN14-AS1 (HGNC:55953): (CLDN14 antisense RNA 1)

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=0.13250381).
• BP6: Variant 21-36461191-T-C is Benign according to our data. Variant chr21-36461191-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 505062.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146079.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	NM_001146079.2	MANE Select	c.505A>G	p.Ile169Val	missense	Exon 2 of 2	NP_001139551.1
	CLDN14	NM_001146077.2		c.505A>G	p.Ile169Val	missense	Exon 3 of 3	NP_001139549.1
	CLDN14	NM_001146078.3		c.505A>G	p.Ile169Val	missense	Exon 3 of 3	NP_001139550.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	ENST00000399135.6	TSL:1 MANE Select	c.505A>G	p.Ile169Val	missense	Exon 2 of 2	ENSP00000382087.1
	CLDN14	ENST00000342108.2	TSL:1	c.505A>G	p.Ile169Val	missense	Exon 3 of 3	ENSP00000339292.2
	CLDN14	ENST00000399136.5	TSL:1	c.505A>G	p.Ile169Val	missense	Exon 3 of 3	ENSP00000382088.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250488 AF XY: 0.00

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461610 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727064

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111812

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 09, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ile169Val in exon 3 of CLDN14: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 2 mammals (shrew and platypus) and many other species have a valine (Val) at this position despite high nearby amino acid conservation. In addition, compu tational prediction tools do not suggest a high likelihood of impact to the prot ein.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.53	N
PhyloP100		2.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
Sift4G	Benign	0.86	T
Polyphen		0.0050	B
Vest4		0.027
MutPred		0.52		Gain of sheet (P = 0.0344)
MVP		0.69
MPC		0.23
ClinPred		0.12	T
GERP RS		3.1
Varity_R		0.073
gMVP		0.38
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1555841637; hg19: chr21-37833489;