rs2245216

Positions:

chr9-100252902-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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]

INVS links:

INVS (HGNC:):

INVS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	MANE	Protein	UniProt
INVS	NM_014425.5 linkuse as main transcript	c.1235-5T>C	splice_region_variant, intron_variant	ENST00000262457.7	NP_055240.2	Q9Y283-1A0A024R153
INVS	NM_001318381.2 linkuse as main transcript	c.947-5T>C	splice_region_variant, intron_variant		NP_001305310.1	Q2M1I4
INVS	NM_001318382.2 linkuse as main transcript	c.257-5T>C	splice_region_variant, intron_variant		NP_001305311.1
INVS	NR_134606.2 linkuse as main transcript	n.1433-5T>C	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7 linkuse as main transcript	c.1235-5T>C		splice_region_variant, intron_variant		1	NM_014425.5	ENSP00000262457.2		Q9Y283-1
INVS	ENST00000262456.6 linkuse as main transcript	c.1235-5T>C		splice_region_variant, intron_variant		5		ENSP00000262456.2		Q9Y283-2

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45497

AN:

151996

Hom.:

7970

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.371

AC XY:

268606

AN XY:

723670

show subpopulations

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.:

AF XY:

0.294

AC XY:

21845

AN XY:

74354

show subpopulations

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

LINK: link

Submissions by phenotype

Infantile nephronophthisis

Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over