rs115640267

Variant names:

• chr9-100104623-C-G
• rs115640267
• NM_014425.5:c.102C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-100104623-C-G
• chr9-100104623-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014425.5(INVS):​c.102C>G​(p.Ile34Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I34I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.102C>G	p.Ile34Met	missense	Exon 2 of 17	NP_055240.2
	INVS	NM_001318381.2		c.-275C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001305310.1
	INVS	NM_001318382.2		c.-888C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 17	NP_001305311.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.102C>G	p.Ile34Met	missense	Exon 2 of 17	ENSP00000262457.2
	INVS	ENST00000374921.3	TSL:1	c.102C>G	p.Ile34Met	missense	Exon 2 of 4	ENSP00000364056.3
	INVS	ENST00000262456.6	TSL:5	c.102C>G	p.Ile34Met	missense	Exon 2 of 18	ENSP00000262456.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455084 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724298

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105820

Other (OTH) AF: 0.00 AC: 0 AN: 60190

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.082	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.72		Gain of disorder (P = 0.0537)
MVP		0.68
MPC		0.78
ClinPred		0.81	D
GERP RS		-4.7
Varity_R		0.21
gMVP		0.61
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.92		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs115640267; hg19: chr9-102866905;