Genetic Variant NM_014425.5:c.102C>T (chr9-100104623-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014425.5(INVS):c.102C>T(p.Ile34Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,607,312 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 11 hom. )

Consequence

INVS
NM_014425.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.00

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 9-100104623-C-T is Benign according to our data. Variant chr9-100104623-C-T is described in ClinVar as Benign. ClinVar VariationId is 167194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00512 (780/152232) while in subpopulation AFR AF = 0.0178 (740/41546). AF 95% confidence interval is 0.0167. There are 2 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.102C>T	p.Ile34Ile	synonymous	Exon 2 of 17	NP_055240.2
INVS	NM_001318381.2		c.-275C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001305310.1
INVS	NM_001318382.2		c.-888C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 17	NP_001305311.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INVS	ENST00000262457.7	TSL:1 MANE Select	c.102C>T	p.Ile34Ile	synonymous	Exon 2 of 17	ENSP00000262457.2
INVS	ENST00000374921.3	TSL:1	c.102C>T	p.Ile34Ile	synonymous	Exon 2 of 4	ENSP00000364056.3
INVS	ENST00000262456.6	TSL:5	c.102C>T	p.Ile34Ile	synonymous	Exon 2 of 18	ENSP00000262456.2

Frequencies

GnomAD3 genomes

AF:

0.00511

AC:

778

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00148

AC:

371

AN:

251412

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.0203

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000567

AC:

825

AN:

1455080

Hom.:

Cov.:

AF XY:

0.000490

AC XY:

355

AN XY:

724296

show subpopulations

African (AFR)

AF:

0.0180

AC:

599

AN:

33328

American (AMR)

AF:

0.000895

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26086

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000968

AC:

107

AN:

1105820

Other (OTH)

AF:

0.00111

AC:

AN:

60190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00512

AC:

780

AN:

152232

Hom.:

Cov.:

AF XY:

0.00472

AC XY:

351

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0178

AC:

740

AN:

41546

American (AMR)

AF:

0.00137

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

158

197

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:

0.00293

Hom.:

Bravo

AF:

0.00625

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 15, 2022

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

9.3

(source)

DANN

Benign

0.71

PhyloP100

0.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over