rs2787374

chr9-100292669-T-Cchr9-100292669-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014425.5(INVS):c.2412T>C(p.Ser804=) 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:8
• Conservation: PhyloP100: 0.479

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 95597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100292669-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.2412T>C	p.Ser804=	synonymous_variant	14/17	ENST00000262457.7
INVS	NM_001318381.2	c.2124T>C	p.Ser708=	synonymous_variant	15/18
INVS	NM_001318382.2	c.1434T>C	p.Ser478=	synonymous_variant	14/17
INVS	NR_134606.2	n.2561T>C		non_coding_transcript_exon_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.2412T>C	p.Ser804=	synonymous_variant	14/17	1	NM_014425.5	A2
INVS	ENST00000262456.6	c.2179+233T>C		intron_variant		5		P4

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

GnomAD3 exomes AF: 0.454 AC: 113091 AN: 248964 Hom.: 29084 AF XY: 0.457 AC XY: 61547 AN XY: 134790

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 SAS exome AF: 0.298

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

Gnomad4 AFR exome AF: 0.594

Gnomad4 AMR exome AF: 0.278

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.0929

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.538

Gnomad4 NFE exome AF: 0.585

Gnomad4 OTH exome AF: 0.515

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

Gnomad4 AFR AF: 0.594

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.528

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.522

Alfa AF: 0.548 Hom.: 41428

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile nephronophthisis Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	10
Dann	Benign	0.72

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

LitVar

Other links and lift over

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