19-51367513-A-C

Variant names:

• chr19-51367513-A-C
• NM_152353.3:c.374T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152353.3(CLDND2):​c.374T>G​(p.Phe125Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CLDND2 NM_152353.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88
• Publications: 0 publications found

Genes affected

CLDND2 (HGNC:28511): (claudin domain containing 2) Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269403 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152353.3. 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
	CLDND2	NM_152353.3	MANE Select	c.374T>G	p.Phe125Cys	missense	Exon 3 of 4	NP_689566.1	Q8NHS1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDND2	ENST00000291715.5	TSL:1 MANE Select	c.374T>G	p.Phe125Cys	missense	Exon 3 of 4	ENSP00000291715.1	Q8NHS1
	ENSG00000269403	ENST00000600067.1	TSL:5	n.115+373T>G		intron	N/A	ENSP00000469452.1	M0QXX7
	CLDND2	ENST00000601435.1	TSL:3	c.374T>G	p.Phe125Cys	missense	Exon 4 of 5	ENSP00000472077.1	Q8NHS1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458174 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 725032

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 85462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53138

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110238

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 32

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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.63
MutPred		0.70		Loss of sheet (P = 0.0817)
MVP		0.68
MPC		0.60
ClinPred		0.87	D
GERP RS		3.6
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.59
Mutation Taster		=93/7	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

hg19: chr19-51870767;