rs2245216

Variant names:

• chr9-100252902-T-C
• rs2245216
• NM_014425.5:c.1235-5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014425.5(INVS):​c.1235-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,605,678 control chromosomes in the GnomAD database, including 115,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7966 hom., cov: 32)
  • Exomes 𝑓: 0.37 (107244 hom.)
• Consequence: INVS NM_014425.5 splice_region, intron
• Scores: Splicing: ADA: 0.0008594
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.45
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-100252902-T-C is Benign according to our data. Variant chr9-100252902-T-C is described in ClinVar as Benign. ClinVar VariationId is 95594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 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.1235-5T>C		splice_region intron	N/A	NP_055240.2
	INVS	NM_001318381.2		c.947-5T>C		splice_region intron	N/A	NP_001305310.1
	INVS	NM_001318382.2		c.257-5T>C		splice_region intron	N/A	NP_001305311.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.1235-5T>C		splice_region intron	N/A	ENSP00000262457.2
	INVS	ENST00000262456.6	TSL:5	c.1235-5T>C		splice_region intron	N/A	ENSP00000262456.2

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45497 AN: 151996 Hom.: 7970 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.308 AC: 76962 AN: 249808 AF XY: 0.315

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.348

GnomAD4 exome AF: 0.373 AC: 542054 AN: 1453564 Hom.: 107244 Cov.: 29 AF XY: 0.371 AC XY: 268606 AN XY: 723670

African (AFR) AF: 0.134 AC: 4466 AN: 33310

American (AMR) AF: 0.181 AC: 8066 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 8998 AN: 26068

East Asian (EAS) AF: 0.0797 AC: 3155 AN: 39608

South Asian (SAS) AF: 0.228 AC: 19574 AN: 86020

European-Finnish (FIN) AF: 0.390 AC: 20805 AN: 53354

Middle Eastern (MID) AF: 0.344 AC: 1979 AN: 5750

European-Non Finnish (NFE) AF: 0.411 AC: 454460 AN: 1104728

Other (OTH) AF: 0.342 AC: 20551 AN: 60112

GnomAD4 genome AF: 0.299 AC: 45499 AN: 152114 Hom.: 7966 Cov.: 32 AF XY: 0.294 AC XY: 21845 AN XY: 74354

African (AFR) AF: 0.142 AC: 5913 AN: 41544

American (AMR) AF: 0.259 AC: 3955 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1149 AN: 3462

East Asian (EAS) AF: 0.104 AC: 541 AN: 5188

South Asian (SAS) AF: 0.213 AC: 1029 AN: 4824

European-Finnish (FIN) AF: 0.372 AC: 3929 AN: 10568

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27633 AN: 67960

Other (OTH) AF: 0.321 AC: 677 AN: 2110

Alfa AF: 0.360 Hom.: 8786

Bravo AF: 0.287

Asia WGS AF: 0.186 AC: 649 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.81
CADD	Benign	12
DANN	Benign	0.57
PhyloP100		1.5
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00086
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.020		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: rs2245216; hg19: chr9-103015184; COSMIC: COSV52439719;