chr7-90413403-A-G

Variant names:

• chr7-90413403-A-G
• rs1797010396
• NM_001185072.3:c.727A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001185072.3(CLDN12):​c.727A>G​(p.Thr243Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLDN12 NM_001185072.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.108
• Publications: 0 publications found

Genes affected

CLDN12 (HGNC:2034): (claudin 12) 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 gene is expressed in the inner ear and bladder epithelium, and it is over-expressed in colorectal carcinomas. This protein and claudin 2 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Multiple alternatively spliced transcript variants encoding the same protein have been found.[provided by RefSeq, Sep 2011]

ENSG00000273299 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029093236).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001185072.3. 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
	CLDN12	NM_001185072.3	MANE Select	c.727A>G	p.Thr243Ala	missense	Exon 4 of 4	NP_001172001.1	P56749
	CLDN12	NM_001185073.3		c.727A>G	p.Thr243Ala	missense	Exon 3 of 3	NP_001172002.1	P56749
	CLDN12	NM_012129.5		c.727A>G	p.Thr243Ala	missense	Exon 3 of 3	NP_036261.1	P56749

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN12	ENST00000496677.6	TSL:1 MANE Select	c.727A>G	p.Thr243Ala	missense	Exon 4 of 4	ENSP00000419053.1	P56749
	CLDN12	ENST00000287916.8	TSL:1	c.727A>G	p.Thr243Ala	missense	Exon 3 of 3	ENSP00000287916.4	P56749
	CLDN12	ENST00000394605.2	TSL:2	c.727A>G	p.Thr243Ala	missense	Exon 3 of 3	ENSP00000378103.1	P56749

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460296 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726106

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110840

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

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	0.064
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.5
DANN	Benign	0.53
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.11
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.087
Sift	Benign	0.27	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.022
MutPred		0.18		Loss of sheet (P = 0.0181)
MVP		0.43
ClinPred		0.046	T
GERP RS		-2.7
Varity_R		0.029
gMVP		0.41
Mutation Taster		=99/1	polymorphism

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: rs1797010396; hg19: chr7-90042717;