9-100292669-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, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

Sel.	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

Sel.	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	Q9Y283-1
	INVS	ENST00000885857.1		c.2412T>C	p.Ser804Ser	synonymous	Exon 15 of 18	ENSP00000555916.1
	INVS	ENST00000885859.1		c.2412T>C	p.Ser804Ser	synonymous	Exon 15 of 18	ENSP00000555918.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Infantile nephronophthisis (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Nephronophthisis (1)

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;