1-158088319-C-G

Variant names:

• chr1-158088319-C-G
• rs6427419
• NM_018240.7:c.917-8C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018240.7(KIRREL1):​c.917-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: KIRREL1 NM_018240.7 splice_region, intron
• Scores: Splicing: ADA: 0.0009915
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339
• Publications: 17 publications found

Genes affected

KIRREL1 (HGNC:15734): (kirre like nephrin family adhesion molecule 1) NEPH1 is a member of the nephrin-like protein family, which includes NEPH2 (MIM 607761) and NEPH3 (MIM 607762). The cytoplasmic domains of these proteins interact with the C terminus of podocin (NPHS2; MIM 604766), and the genes are expressed in kidney podocytes, cells involved in ensuring size- and charge-selective ultrafiltration (Sellin et al., 2003 [PubMed 12424224]).[supplied by OMIM, Mar 2008]

KIRREL1 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 23

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIRREL1	NM_018240.7	c.917-8C>G		splice_region_variant, intron_variant	Intron 7 of 14	ENST00000359209.11	NP_060710.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIRREL1	ENST00000359209.11	c.917-8C>G		splice_region_variant, intron_variant	Intron 7 of 14	1	NM_018240.7	ENSP00000352138.6
KIRREL1	ENST00000360089.8	c.425-8C>G		splice_region_variant, intron_variant	Intron 5 of 12	1		ENSP00000353202.4
KIRREL1	ENST00000368173.7	c.617-8C>G		splice_region_variant, intron_variant	Intron 5 of 12	2		ENSP00000357155.4
KIRREL1	ENST00000368172.2	c.563-8C>G		splice_region_variant, intron_variant	Intron 4 of 11	2		ENSP00000357154.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.5
DANN	Benign	0.58
PhyloP100		-0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00099
dbscSNV1_RF	Benign	0.070
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: rs6427419; hg19: chr1-158058109;