chr9-100284480-G-T

Position:

• chr9-100284480-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014425.5(INVS):​c.1945G>T​(p.Val649Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V649M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05771321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.1945G>T	p.Val649Leu	missense_variant	13/17	ENST00000262457.7
INVS	NM_001318381.2	c.1657G>T	p.Val553Leu	missense_variant	14/18
INVS	NM_001318382.2	c.967G>T	p.Val323Leu	missense_variant	13/17
INVS	NR_134606.2	n.2143G>T		non_coding_transcript_exon_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.1945G>T	p.Val649Leu	missense_variant	13/17	1	NM_014425.5	A2
INVS	ENST00000262456.6	c.1945G>T	p.Val649Leu	missense_variant	13/18	5		P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.19
DANN	Benign	0.70
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.010
Sift	Benign	0.27	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0060	B;B
Vest4		0.13
MutPred		0.20		Gain of glycosylation at P645 (P = 0.1722);Gain of glycosylation at P645 (P = 0.1722);
MVP		0.11
MPC		0.23
ClinPred		0.10	T
GERP RS		-3.2
Varity_R		0.043
gMVP		0.043

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: rs115042730; hg19: chr9-103046762;