Genetic Variant NM_001146079.2:c.-81-567T>C (chr21-36462343-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001146079.2(CLDN14):c.-81-567T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 151,930 control chromosomes in the GnomAD database, including 8,358 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 8358 hom., cov: 31)

Consequence

CLDN14
NM_001146079.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.526

Publications

11 publications found

Variant links:

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]

CLDN14 links:

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

LNCTSI links:

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

CLDN14-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN14	NM_001146079.2 link	c.-81-567T>C		intron_variant	Intron 1 of 1	ENST00000399135.6	NP_001139551.1	O95500

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6 link	c.-81-567T>C		intron_variant	Intron 1 of 1	1	NM_001146079.2	ENSP00000382087.1		O95500

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46085

AN:

151812

Hom.:

8319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.497

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.251

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00751

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.210

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.251

Gnomad OTH

AF:

0.309

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.304

AC:

46175

AN:

151930

Hom.:

8358

Cov.:

AF XY:

0.295

AC XY:

21913

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.498

AC:

20606

AN:

41374

American (AMR)

AF:

0.250

AC:

3819

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

834

AN:

3472

East Asian (EAS)

AF:

0.00753

AC:

AN:

5178

South Asian (SAS)

AF:

0.148

AC:

715

AN:

4816

European-Finnish (FIN)

AF:

0.210

AC:

2222

AN:

10574

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.251

AC:

17082

AN:

67940

Other (OTH)

AF:

0.306

AC:

646

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1458

2917

4375

5834

7292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

440

880

1320

1760

2200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.285

Hom.:

4012

Bravo

AF:

0.314

Asia WGS

AF:

0.124

AC:

432

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over