chr7-73831485-T-C

Variant names:

• chr7-73831485-T-C
• rs1788030483
• NM_001305.5:c.284T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001305.5(CLDN4):​c.284T>C​(p.Val95Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CLDN4 NM_001305.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26
• Publications: 0 publications found

Genes affected

CLDN4 (HGNC:2046): (claudin 4) The protein encoded by this intronless gene belongs to the claudin family. Claudins are integral membrane proteins that are components of the epithelial cell tight junctions, which regulate movement of solutes and ions through the paracellular space. This protein is a high-affinity receptor for Clostridium perfringens enterotoxin (CPE) and may play a role in internal organ development and function during pre- and postnatal life. This gene is deleted in Williams-Beuren syndrome, a neurodevelopmental disorder affecting multiple systems. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305.5. 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
	CLDN4	NM_001305.5	MANE Select	c.284T>C	p.Val95Ala	missense	Exon 1 of 1	NP_001296.1	Q75L80

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN4	ENST00000340958.4	TSL:6 MANE Select	c.284T>C	p.Val95Ala	missense	Exon 1 of 1	ENSP00000342445.2	O14493
	CLDN4	ENST00000431918.1	TSL:2	c.284T>C	p.Val95Ala	missense	Exon 2 of 2	ENSP00000388639.1	O14493
	CLDN4	ENST00000435050.1	TSL:2	c.284T>C	p.Val95Ala	missense	Exon 2 of 2	ENSP00000409544.1	O14493

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 34

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.29
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.081
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.2	L
PhyloP100		4.3
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.15	B
Vest4		0.25
MutPred		0.69		Loss of stability (P = 0.1356)
MVP		0.78
MPC		0.69
ClinPred		0.96	D
GERP RS		5.4
PromoterAI		-0.0022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.56
Mutation Taster		=47/53	disease causing

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: rs1788030483; hg19: chr7-73245815;