rs2245216

Variant names:

• chr9-100252902-T-C
• rs2245216
• NM_014425.5:c.1235-5T>C

Variant summary

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

The NM_014425.5(INVS):​c.1235-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,605,678 control chromosomes in the GnomAD database, including 115,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7966 hom., cov: 32)
  • Exomes 𝑓: 0.37 (107244 hom.)
• Consequence: INVS NM_014425.5 splice_region, intron
• Scores: Splicing: ADA: 0.0008594
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.45

Genes affected

INVS (HGNC:17870): (inversin) This gene encodes a protein containing multiple ankyrin domains and two IQ calmodulin-binding domains. The encoded protein may function in renal tubular development and function, and in left-right axis determination. This protein interacts with nephrocystin and infers a connection between primary cilia function and left-right axis determination. A similar protein in mice interacts with calmodulin. Mutations in this gene have been associated with nephronophthisis type 2. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-100252902-T-C is Benign according to our data. Variant chr9-100252902-T-C is described in ClinVar as [Benign]. Clinvar id is 95594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100252902-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INVS	NM_014425.5	c.1235-5T>C		splice_region_variant, intron_variant	Intron 9 of 16	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.947-5T>C		splice_region_variant, intron_variant	Intron 10 of 17		NP_001305310.1
INVS	NM_001318382.2	c.257-5T>C		splice_region_variant, intron_variant	Intron 9 of 16		NP_001305311.1
INVS	NR_134606.2	n.1433-5T>C		splice_region_variant, intron_variant	Intron 9 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.1235-5T>C		splice_region_variant, intron_variant	Intron 9 of 16	1	NM_014425.5	ENSP00000262457.2
INVS	ENST00000262456.6	c.1235-5T>C		splice_region_variant, intron_variant	Intron 9 of 17	5		ENSP00000262456.2

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45497 AN: 151996 Hom.: 7970 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.308 AC: 76962 AN: 249808 Hom.: 13733 AF XY: 0.315 AC XY: 42544 AN XY: 134956

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.223

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.348

GnomAD4 exome AF: 0.373 AC: 542054 AN: 1453564 Hom.: 107244 Cov.: 29 AF XY: 0.371 AC XY: 268606 AN XY: 723670

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.0797

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.411

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.299 AC: 45499 AN: 152114 Hom.: 7966 Cov.: 32 AF XY: 0.294 AC XY: 21845 AN XY: 74354

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.321

Alfa AF: 0.360 Hom.: 6472

Bravo AF: 0.287

Asia WGS AF: 0.186 AC: 649 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile nephronophthisis Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Apr 02, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00086
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.020		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: rs2245216; hg19: chr9-103015184; COSMIC: COSV52439719;