chr19-35859572-G-A

Position:

• chr19-35859572-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199180.4(KIRREL2):​c.614G>A​(p.Arg205Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,614,094 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (87 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (66 hom.)
• Consequence: KIRREL2 NM_199180.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071804225).
• BP6: Variant 19-35859572-G-A is Benign according to our data. Variant chr19-35859572-G-A is described in ClinVar as [Benign]. Clinvar id is 777469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIRREL2	NM_199180.4	c.614G>A	p.Arg205Gln	missense_variant	5/15	ENST00000360202.10	NP_954649.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIRREL2	ENST00000360202.10	c.614G>A	p.Arg205Gln	missense_variant	5/15	1	NM_199180.4	ENSP00000353331	P1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2613 AN: 152138 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00436 AC: 1095 AN: 251418 Hom.: 25 AF XY: 0.00319 AC XY: 434 AN XY: 135876

Gnomad AFR exome AF: 0.0587

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00165 AC: 2414 AN: 1461838 Hom.: 66 Cov.: 31 AF XY: 0.00144 AC XY: 1047 AN XY: 727216

Gnomad4 AFR exome AF: 0.0582

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.0172 AC: 2614 AN: 152256 Hom.: 87 Cov.: 32 AF XY: 0.0166 AC XY: 1235 AN XY: 74434

Gnomad4 AFR AF: 0.0599

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00305 Hom.: 33

Bravo AF: 0.0196

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0533 AC: 235

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00534 AC: 649

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	-0.023
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D;.;D
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	.;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.17	.;T;T;T
Sift4G	Benign	0.078	T;T;T;T
Vest4		0.31
MVP		0.82
MPC		1.1
ClinPred		0.014	T
GERP RS		3.7
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34494265; hg19: chr19-36350474;