rs2787374

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.479

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
INVS	NM_014425.5 linkuse as main transcript	c.2412T>C	p.Ser804=	synonymous_variant	14/17	ENST00000262457.7
INVS	NM_001318381.2 linkuse as main transcript	c.2124T>C	p.Ser708=	synonymous_variant	15/18
INVS	NM_001318382.2 linkuse as main transcript	c.1434T>C	p.Ser478=	synonymous_variant	14/17
INVS	NR_134606.2 linkuse as main transcript	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 linkuse as main transcript	c.2412T>C	p.Ser804=	synonymous_variant	14/17	1	NM_014425.5	A2	Q9Y283-1
INVS	ENST00000262456.6 linkuse as main transcript	c.2179+233T>C		intron_variant		5		P4	Q9Y283-2

Frequencies

GnomAD3 genomes

AF:

0.531

AC:

80672

AN:

151808

Hom.:

22408

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.533

AC XY:

387350

AN XY:

727222

show subpopulations

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.:

AF XY:

0.520

AC XY:

38597

AN XY:

74232

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	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	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not specified

Benign:2

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

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over