rs758278039

Variant names:

• chr19-35860604-G-A
• NM_199180.4:c.865G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-35860604-G-A
• chr19-35860604-G-C
• chr19-35860604-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_199180.4(KIRREL2):​c.865G>A​(p.Val289Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,474 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V289L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KIRREL2 NM_199180.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIRREL2	NM_199180.4	c.865G>A	p.Val289Met	missense_variant	Exon 7 of 15	ENST00000360202.10	NP_954649.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIRREL2	ENST00000360202.10	c.865G>A	p.Val289Met	missense_variant	Exon 7 of 15	1	NM_199180.4	ENSP00000353331.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451474 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.85	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	.;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Vest4		0.63
MutPred		0.77		Gain of catalytic residue at V289 (P = 0.0227);.;Gain of catalytic residue at V289 (P = 0.0227);Gain of catalytic residue at V289 (P = 0.0227);
MVP		0.35
MPC		1.5
ClinPred		0.99	D
GERP RS		4.0
gMVP		0.71

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36351506; COSMIC: COSV52876149; COSMIC: COSV52876149;