rs76868679

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014425.5(INVS):c.2402G>A(p.Gly801Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,614,144 control chromosomes in the GnomAD database, including 1,307 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 Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 98 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1209 hom. )

Consequence

INVS
NM_014425.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.760

Publications

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

INVS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_014425.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.002002865).

BP6

Variant 9-100292659-G-A is Benign according to our data. Variant chr9-100292659-G-A is described in ClinVar as Benign. ClinVar VariationId is 167195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014425.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INVS	NM_014425.5	MANE Select	c.2402G>A	p.Gly801Glu	missense	Exon 14 of 17	NP_055240.2
INVS	NM_001318381.2		c.2114G>A	p.Gly705Glu	missense	Exon 15 of 18	NP_001305310.1
INVS	NM_001318382.2		c.1424G>A	p.Gly475Glu	missense	Exon 14 of 17	NP_001305311.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INVS	ENST00000262457.7	TSL:1 MANE Select	c.2402G>A	p.Gly801Glu	missense	Exon 14 of 17	ENSP00000262457.2	Q9Y283-1
INVS	ENST00000885857.1		c.2402G>A	p.Gly801Glu	missense	Exon 15 of 18	ENSP00000555916.1
INVS	ENST00000885859.1		c.2402G>A	p.Gly801Glu	missense	Exon 15 of 18	ENSP00000555918.1

Frequencies

GnomAD3 genomes

AF:

0.0279

AC:

4249

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00821

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.0338

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0426

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0275

AC:

6860

AN:

249112

AF XY:

0.0278

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.0240

Gnomad ASJ exome

AF:

0.0250

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.0438

Gnomad OTH exome

AF:

0.0335

GnomAD4 exome

AF:

0.0386

AC:

56400

AN:

1461868

Hom.:

1209

Cov.:

AF XY:

0.0378

AC XY:

27524

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00624

AC:

209

AN:

33480

American (AMR)

AF:

0.0254

AC:

1138

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0237

AC:

620

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00547

AC:

472

AN:

86256

European-Finnish (FIN)

AF:

0.0226

AC:

1206

AN:

53420

Middle Eastern (MID)

AF:

0.0621

AC:

358

AN:

5768

European-Non Finnish (NFE)

AF:

0.0452

AC:

50275

AN:

1111988

Other (OTH)

AF:

0.0351

AC:

2120

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

3416

6831

10247

13662

17078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1836

3672

5508

7344

9180

<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:

0.0279

AC:

4250

AN:

152276

Hom.:

Cov.:

AF XY:

0.0267

AC XY:

1989

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00821

AC:

341

AN:

41554

American (AMR)

AF:

0.0337

AC:

515

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00477

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0192

AC:

204

AN:

10618

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0426

AC:

2899

AN:

68010

Other (OTH)

AF:

0.0426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

215

429

644

858

1073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0388

Hom.:

446

Bravo

AF:

0.0293

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0459

EpiControl

AF:

0.0445

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Infantile nephronophthisis (1)

Kidney disorder (1)

Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.13

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

0.76

PrimateAI

Benign

0.32

PROVEAN

Benign

0.33

REVEL

Benign

0.042

Sift

Benign

1.0

Sift4G

Benign

0.54

Varity_R

0.025

gMVP

0.035

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over