9-100292825-G-T

Variant names:

• chr9-100292825-G-T
• rs886038604
• NM_014425.5:c.2568G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014425.5(INVS):​c.2568G>T​(p.Arg856Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. R856R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.834
• 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, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1821284).

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.2568G>T	p.Arg856Ser	missense	Exon 14 of 17	NP_055240.2
	INVS	NM_001318381.2		c.2280G>T	p.Arg760Ser	missense	Exon 15 of 18	NP_001305310.1
	INVS	NM_001318382.2		c.1590G>T	p.Arg530Ser	missense	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.2568G>T	p.Arg856Ser	missense	Exon 14 of 17	ENSP00000262457.2	Q9Y283-1
	INVS	ENST00000885857.1		c.2568G>T	p.Arg856Ser	missense	Exon 15 of 18	ENSP00000555916.1
	INVS	ENST00000885859.1		c.2568G>T	p.Arg856Ser	missense	Exon 15 of 18	ENSP00000555918.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.83
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.14
Sift	Benign	0.060	T
Sift4G	Benign	0.38	T
Polyphen		0.68	P
Vest4		0.19
MutPred		0.13		Gain of phosphorylation at R856 (P = 0.0285)
MVP		0.71
MPC		0.44
ClinPred		0.35	T
GERP RS		1.4
Varity_R		0.10
gMVP		0.37
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs886038604; hg19: chr9-103055107; COSMIC: COSV52447121;