NM_001305.5:c.128C>A

Variant names:

• chr7-73831329-C-A
• rs561546540
• NM_001305.5:c.128C>A

Variant summary

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

The NM_001305.5(CLDN4):​c.128C>A​(p.Ser43*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLDN4 NM_001305.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 2 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.128C>A	p.Ser43*	stop_gained	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.128C>A	p.Ser43*	stop_gained	Exon 1 of 1	ENSP00000342445.2	O14493
	CLDN4	ENST00000431918.1	TSL:2	c.128C>A	p.Ser43*	stop_gained	Exon 2 of 2	ENSP00000388639.1	O14493
	CLDN4	ENST00000435050.1	TSL:2	c.128C>A	p.Ser43*	stop_gained	Exon 2 of 2	ENSP00000409544.1	O14493

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251180 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461634 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33470

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111926

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

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000508 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		7.9
Vest4		0.59
GERP RS		5.5
PromoterAI		-0.022	Neutral
Mutation Taster		=21/179	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: rs561546540; hg19: chr7-73245659; COSMIC: COSV99936569; COSMIC: COSV99936569;