NM_199180.4:c.650C>T

Variant names:

• chr19-35859608-C-T
• rs202029599
• NM_199180.4:c.650C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_199180.4(KIRREL2):​c.650C>T​(p.Thr217Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,326 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: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KIRREL2 NM_199180.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23
• Publications: 0 publications found

Genes affected

KIRREL2 (HGNC:18816): (kirre like nephrin family adhesion molecule 2) This gene encodes a type I transmembrane protein and member of the immunoglobulin superfamily of cell adhesion molecules. The encoded protein localizes to adherens junctions in pancreatic beta cells and regulates insulin secretion. Autoantibodies against the encoded protein have been detected in serum from patients with type 1 diabetes. This gene may also play a role in glomerular development and decreased expression of this gene has been observed in human glomerular diseases. This gene and the related opposite-strand gene nephrin (GeneID: 527362) are regulated by a bidirectional promoter. [provided by RefSeq, Jul 2016]

NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]

NPHS1 Gene-Disease associations (from GenCC):

• congenital nephrotic syndrome, Finnish type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199180.4. 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
	KIRREL2	NM_199180.4	MANE Select	c.650C>T	p.Thr217Ile	missense	Exon 5 of 15	NP_954649.3	Q6UWL6-1
	KIRREL2	NM_001363667.2		c.650C>T	p.Thr217Ile	missense	Exon 5 of 14	NP_001350596.1	K7EJS8
	KIRREL2	NM_001329530.2		c.500C>T	p.Thr167Ile	missense	Exon 4 of 14	NP_001316459.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIRREL2	ENST00000360202.10	TSL:1 MANE Select	c.650C>T	p.Thr217Ile	missense	Exon 5 of 15	ENSP00000353331.4	Q6UWL6-1
	KIRREL2	ENST00000592409.5	TSL:1	c.650C>T	p.Thr217Ile	missense	Exon 5 of 14	ENSP00000465305.1	K7EJS8
	KIRREL2	ENST00000262625.7	TSL:1	c.650C>T	p.Thr217Ile	missense	Exon 5 of 16	ENSP00000262625.6	Q6UWL6-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251262 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: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

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	0.35
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.59	D
PhyloP100		3.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.079	T
Vest4		0.69
MVP		0.97
MPC		0.94
ClinPred		0.99	D
GERP RS		4.7
gMVP		0.69
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs202029599; hg19: chr19-36350510;