NM_199180.4:c.790G>C

Variant names:

• chr19-35860529-G-C
• rs762476394
• NM_199180.4:c.790G>C

Variant summary

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

The NM_199180.4(KIRREL2):​c.790G>C​(p.Gly264Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,206 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KIRREL2 NM_199180.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.21
• Publications: 1 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 2 ACMG points.

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

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.790G>C	p.Gly264Arg	missense	Exon 7 of 15	NP_954649.3	Q6UWL6-1
	KIRREL2	NM_001363667.2		c.790G>C	p.Gly264Arg	missense	Exon 7 of 14	NP_001350596.1	K7EJS8
	KIRREL2	NM_001329530.2		c.640G>C	p.Gly214Arg	missense	Exon 6 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.790G>C	p.Gly264Arg	missense	Exon 7 of 15	ENSP00000353331.4	Q6UWL6-1
	KIRREL2	ENST00000592409.5	TSL:1	c.790G>C	p.Gly264Arg	missense	Exon 7 of 14	ENSP00000465305.1	K7EJS8
	KIRREL2	ENST00000262625.7	TSL:1	c.790G>C	p.Gly264Arg	missense	Exon 7 of 16	ENSP00000262625.6	Q6UWL6-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	0.0081	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-1.1	T
PhyloP100		5.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.35
Sift	Benign	0.21	T
Sift4G	Pathogenic	0.0	D
Vest4		0.71
MutPred		0.59		Gain of MoRF binding (P = 0.0132)
MVP		0.37
MPC		1.5
ClinPred		0.99	D
GERP RS		4.0
gMVP		0.74
Mutation Taster		=38/62	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: rs762476394; hg19: chr19-36351431;