rs147452898

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.1948G>C(p.Ala650Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,614,130 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. A650A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0043 ( 25 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.716

Publications

4 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:

LOC124902235 (HGNC:):

LOC124902235 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=0.009577215).

BP6

Variant 9-100284483-G-C is Benign according to our data. Variant chr9-100284483-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95596.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 = 0.00375 (571/152360) while in subpopulation NFE AF = 0.00404 (275/68036). AF 95% confidence interval is 0.00365. There are 4 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.1948G>C	p.Ala650Pro	missense_variant	Exon 13 of 17	ENST00000262457.7	NP_055240.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7 link	c.1948G>C	p.Ala650Pro	missense_variant	Exon 13 of 17	1	NM_014425.5	ENSP00000262457.2
INVS	ENST00000262456.6 link	c.1948G>C	p.Ala650Pro	missense_variant	Exon 13 of 18	5		ENSP00000262456.2

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00404

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00399

AC:

998

AN:

250398

AF XY:

0.00391

show subpopulations

Gnomad AFR exome

AF:

0.000434

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0222

Gnomad NFE exome

AF:

0.00392

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00425

AC:

6217

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

2997

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33474

American (AMR)

AF:

0.000828

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000487

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0188

AC:

1004

AN:

53398

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00440

AC:

4889

AN:

1111968

Other (OTH)

AF:

0.00361

AC:

218

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

396

792

1187

1583

1979

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

376

564

752

940

<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:

0.00375

AC:

571

AN:

152360

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

309

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000817

AC:

AN:

41600

American (AMR)

AF:

0.00183

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0213

AC:

226

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00404

AC:

275

AN:

68036

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00319

Hom.:

Bravo

AF:

0.00227

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00330

AC:

400

EpiCase

AF:

0.00344

EpiControl

AF:

0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile nephronophthisis

Benign:3

Apr 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

INVS: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Oct 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kidney disorder

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis

Benign:1

Jan 17, 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

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.67

T;T

MetaRNN

Benign

0.0096

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

M;M

PhyloP100

0.72

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.79

N;N

REVEL

Benign

0.23

Sift

Benign

0.076

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.17

B;P

Vest4

0.19

MVP

0.37

MPC

0.46

ClinPred

0.011

GERP RS

-2.3

Varity_R

0.084

gMVP

0.15

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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