rs2491097

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014425.5(INVS):c.725C>T(p.Ser242Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,613,908 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S242S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0047 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 38 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.91

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

nephronophthisis 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

INVS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015121937).

BP6

Variant 9-100240169-C-T is Benign according to our data. Variant chr9-100240169-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0047 (716/152206) while in subpopulation NFE AF = 0.00652 (443/67996). AF 95% confidence interval is 0.00601. There are 4 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INVS	NM_014425.5 link	c.725C>T	p.Ser242Leu	missense_variant	Exon 6 of 17	ENST00000262457.7	NP_055240.2	Q9Y283-1A0A024R153
INVS	NM_001318381.2 link	c.437C>T	p.Ser146Leu	missense_variant	Exon 7 of 18		NP_001305310.1	Q2M1I4
INVS	NR_134606.2 link	n.923C>T		non_coding_transcript_exon_variant	Exon 6 of 17
INVS	NM_001318382.2 link	c.-265C>T		5_prime_UTR_variant	Exon 6 of 17		NP_001305311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INVS	ENST00000262457.7 link	c.725C>T	p.Ser242Leu	missense_variant	Exon 6 of 17	1	NM_014425.5	ENSP00000262457.2	Q9Y283-1
INVS	ENST00000262456.6 link	c.725C>T	p.Ser242Leu	missense_variant	Exon 6 of 18	5		ENSP00000262456.2	Q9Y283-2
INVS	ENST00000460636.2 link	n.*43C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00471

AC:

716

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00651

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00467

AC:

1173

AN:

251440

AF XY:

0.00461

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00356

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.00636

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00571

AC:

8351

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00557

AC XY:

4048

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.000807

AC:

AN:

33478

American (AMR)

AF:

0.00391

AC:

175

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000255

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0114

AC:

608

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00651

AC:

7239

AN:

1111848

Other (OTH)

AF:

0.00454

AC:

274

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

405

810

1215

1620

2025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00470

AC:

716

AN:

152206

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

368

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41538

American (AMR)

AF:

0.00268

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0124

AC:

131

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00652

AC:

443

AN:

67996

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00550

Hom.:

Bravo

AF:

0.00401

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00456

AC:

553

EpiCase

AF:

0.00523

EpiControl

AF:

0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 25, 2013

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

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

INVS: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nephronophthisis

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Infantile nephronophthisis

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.0062

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.7

L;L

PhyloP100

7.9

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

0.98

D;D

Vest4

0.85

MVP

0.90

MPC

0.78

ClinPred

0.017

GERP RS

5.6

Varity_R

0.39

gMVP

0.37

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over