chr3-190388214-G-T

Variant names:

• chr3-190388214-G-T
• rs763354782
• NM_006580.4:c.-116G>T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_006580.4(CLDN16):c.-116G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000328 (AC=53) in the gnomAD database across 1,613,918 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000334. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: CLDN16 NM_006580.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.0460
• Publications: 1 publications found

Genes affected

CLDN16 (HGNC:2037): (claudin 16) 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. It is found primarily in the kidneys, specifically in the thick ascending limb of Henle, where it acts as either an intercellular pore or ion concentration sensor to regulate the paracellular resorption of magnesium ions. Defects in this gene are a cause of primary hypomagnesemia, which is characterized by massive renal magnesium wasting with hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and renal failure. This gene and the CLDN1 gene are clustered on chromosome 3q28. [provided by RefSeq, Jun 2010]

CLDN16 Gene-Disease associations (from GenCC):

• renal hypomagnesemia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000297357 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000334 — very rare for AR gene (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006580.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	NM_006580.4	MANE Select	c.-116G>T		5_prime_UTR	Exon 1 of 5	NP_006571.2	Q9Y5I7
	CLDN16	NM_001378492.1		c.-93-23G>T		intron	N/A	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.-93-23G>T		intron	N/A	NP_001365422.1	Q9Y5I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000264734.3	TSL:1 MANE Select	c.-116G>T		5_prime_UTR	Exon 1 of 5	ENSP00000264734.3	Q9Y5I7
	CLDN16	ENST00000456423.2	TSL:1	c.-116G>T		5_prime_UTR	Exon 1 of 2	ENSP00000414136.2	F6SGM4
	CLDN16	ENST00000880228.1		c.-116G>T		5_prime_UTR	Exon 1 of 5	ENSP00000550287.1	A0ACI8VBN7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152130	Cov:32
GnomAD2 exomes	AF: 0.0000199	AC:5	Hom:	AN:250932	Cov:
GnomAD4 exome	AF: 0.0000349	AC:51	Hom:0	AN:1461788	Cov:30
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152130	Cov:32
TOPMed (Bravo)	AF: 0.0000227	AC:6	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000178	AC:3	Hom:0	AN:16840	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.0000299	2	66886
SCHEMA(Schizophrenia)	0.00000967	1	103364	0.0000217	4	184658

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary hypomagnesemia (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Uncertain	-	15
AlphaMissense	Benign	-	0.13
BayesDel_addAF	Benign	T	-0.059
BayesDel_noAF	Benign	-	-0.14
CADD	Benign	-	4.8
DANN	Benign	-	0.94
DEOGEN2	Benign	T	0.079
Eigen	Benign	-	-1.1
Eigen_PC	Benign	-	-1.0
FATHMM_MKL	Benign	N	0.11
GPN-Star LLR	N/A	-	-0.34
GPN-Star score	N/A	-	0.34
LIST_S2	Benign	T	0.65
M_CAP	Benign	D	0.052
MetaRNN	Benign	T	0.067
MetaSVM	Benign	T	-0.33
MutationAssessor	Benign	N	0.34
PhyloP100	Benign	-	-0.046
PrimateAI	Benign	T	0.26
PromoterAI	N/A	Neutral	-0.0026
PROVEAN	Benign	N	-0.65
REVEL	Uncertain	-	0.30
Sift	Uncertain	D	0.0030
Sift4G	Benign	T	0.066
Varity_R	N/A	-	0.078
VESM-3B	Benign	-	-3.4

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.10
Pangolin gain	Benign	- Position offset: 23	0.10
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 3 of 3 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs763354782;

hg19: chr3-190106003;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar