rs116606949

Positions:

• chr9-100292567-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The ENST00000262457.7(INVS):​c.2310C>T​(p.His770=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,614,124 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: INVS ENST00000262457.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.348

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-100292567-C-T is Benign according to our data. Variant chr9-100292567-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240911.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr9-100292567-C-T is described in Lovd as [Benign]. Variant chr9-100292567-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.348 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00116 (177/152240) while in subpopulation NFE AF= 0.00185 (126/68014). AF 95% confidence interval is 0.00159. There are 1 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INVS	NM_014425.5	c.2310C>T	p.His770=	synonymous_variant	14/17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.2022C>T	p.His674=	synonymous_variant	15/18		NP_001305310.1
INVS	NM_001318382.2	c.1332C>T	p.His444=	synonymous_variant	14/17		NP_001305311.1
INVS	NR_134606.2	n.2459C>T		non_coding_transcript_exon_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.2310C>T	p.His770=	synonymous_variant	14/17	1	NM_014425.5	ENSP00000262457	A2
INVS	ENST00000262456.6	c.2179+131C>T		intron_variant		5		ENSP00000262456	P4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152122 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000865 AC: 216 AN: 249618 Hom.: 0 AF XY: 0.000836 AC XY: 113 AN XY: 135100

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00144 AC: 2100 AN: 1461884 Hom.: 4 Cov.: 31 AF XY: 0.00138 AC XY: 1000 AN XY: 727244

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152240 Hom.: 1 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74438

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.000858

EpiCase AF: 0.00185

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Infantile nephronophthisis Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 16, 2018

- -

Nephronophthisis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.1
DANN	Benign	0.46

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: rs116606949; hg19: chr9-103054849;