chr9-100292669-T-C

Variant names:

• chr9-100292669-T-C
• rs2787374
• NM_014425.5:c.2412T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014425.5(INVS):​c.2412T>C​(p.Ser804Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,613,762 control chromosomes in the GnomAD database, including 244,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S804S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.53 (22447 hom., cov: 31)
  • Exomes 𝑓: 0.54 (221984 hom.)
• Consequence: INVS NM_014425.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.479
• Publications: 19 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-100292669-T-C is Benign according to our data. Variant chr9-100292669-T-C is described in ClinVar as Benign. ClinVar VariationId is 95597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.479 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	NM_014425.5	MANE Select	c.2412T>C	p.Ser804Ser	synonymous	Exon 14 of 17	NP_055240.2
	INVS	NM_001318381.2		c.2124T>C	p.Ser708Ser	synonymous	Exon 15 of 18	NP_001305310.1
	INVS	NM_001318382.2		c.1434T>C	p.Ser478Ser	synonymous	Exon 14 of 17	NP_001305311.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.2412T>C	p.Ser804Ser	synonymous	Exon 14 of 17	ENSP00000262457.2
	INVS	ENST00000262456.6	TSL:5	c.2179+233T>C		intron	N/A	ENSP00000262456.2

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80672 AN: 151808 Hom.: 22408 Cov.: 31

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.520

GnomAD2 exomes AF: 0.454 AC: 113091 AN: 248964 AF XY: 0.457

Gnomad AFR exome AF: 0.588

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.419

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.579

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.538 AC: 786668 AN: 1461836 Hom.: 221984 Cov.: 60 AF XY: 0.533 AC XY: 387350 AN XY: 727222

African (AFR) AF: 0.594 AC: 19871 AN: 33480

American (AMR) AF: 0.278 AC: 12421 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11028 AN: 26136

East Asian (EAS) AF: 0.0929 AC: 3687 AN: 39698

South Asian (SAS) AF: 0.307 AC: 26460 AN: 86256

European-Finnish (FIN) AF: 0.538 AC: 28723 AN: 53414

Middle Eastern (MID) AF: 0.481 AC: 2776 AN: 5768

European-Non Finnish (NFE) AF: 0.585 AC: 650580 AN: 1111970

Other (OTH) AF: 0.515 AC: 31122 AN: 60394

GnomAD4 genome AF: 0.532 AC: 80772 AN: 151926 Hom.: 22447 Cov.: 31 AF XY: 0.520 AC XY: 38597 AN XY: 74232

African (AFR) AF: 0.594 AC: 24598 AN: 41444

American (AMR) AF: 0.415 AC: 6341 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1409 AN: 3470

East Asian (EAS) AF: 0.114 AC: 586 AN: 5160

South Asian (SAS) AF: 0.285 AC: 1372 AN: 4814

European-Finnish (FIN) AF: 0.528 AC: 5559 AN: 10524

Middle Eastern (MID) AF: 0.442 AC: 129 AN: 292

European-Non Finnish (NFE) AF: 0.574 AC: 38984 AN: 67936

Other (OTH) AF: 0.522 AC: 1101 AN: 2110

Alfa AF: 0.549 Hom.: 95644

Bravo AF: 0.527

Asia WGS AF: 0.267 AC: 930 AN: 3478

EpiCase AF: 0.560

EpiControl AF: 0.567

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile nephronophthisis Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Apr 02, 2014

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.72
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2787374; hg19: chr9-103054951; COSMIC: COSV52441342;