16-3013561-T-C

Variant names:

• chr16-3013561-T-C
• NM_020982.4:c.199T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020982.4(CLDN9):​c.199T>C​(p.Tyr67His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLDN9 NM_020982.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

Genes affected

CLDN9 (HGNC:2051): (claudin 9) 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. This protein is one of the entry cofactors for hepatitis C virus. Mouse studies revealed that this gene is required for the preservation of sensory cells in the hearing organ and the gene deficiency is associated with deafness. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN9	NM_020982.4	c.199T>C	p.Tyr67His	missense_variant	Exon 1 of 1	ENST00000445369.3	NP_066192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN9	ENST00000445369.3	c.199T>C	p.Tyr67His	missense_variant	Exon 1 of 1	6	NM_020982.4	ENSP00000398017.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199T>C (p.Y67H) alteration is located in exon 1 (coding exon 1) of the CLDN9 gene. This alteration results from a T to C substitution at nucleotide position 199, causing the tyrosine (Y) at amino acid position 67 to be replaced by a histidine (H). 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	0.39
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.76
Sift	Benign	0.15	T
Sift4G	Benign	0.087	T
Polyphen		0.58	P
Vest4		0.38
MutPred		0.83		Gain of disorder (P = 0.05);
MVP		0.74
MPC		0.18
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.78
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-3063562;