9-100104527-C-A

Position:

• chr9-100104527-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014425.5(INVS):​c.6C>A​(p.Asn2Lys) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00300

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1281099).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INVS	NM_014425.5	c.6C>A	p.Asn2Lys	missense_variant	Exon 2 of 17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.-371C>A		5_prime_UTR_variant	Exon 2 of 18		NP_001305310.1
INVS	NM_001318382.2	c.-984C>A		5_prime_UTR_variant	Exon 2 of 17		NP_001305311.1
INVS	NR_134606.2	n.204C>A		non_coding_transcript_exon_variant	Exon 2 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.6C>A	p.Asn2Lys	missense_variant	Exon 2 of 17	1	NM_014425.5	ENSP00000262457.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2024

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2 of the INVS protein (p.Asn2Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with INVS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1517475). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.88	N;N;N
REVEL	Benign	0.069
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.61	P;P;.
Vest4		0.37
MutPred		0.37		Gain of ubiquitination at N2 (P = 0.0219);Gain of ubiquitination at N2 (P = 0.0219);Gain of ubiquitination at N2 (P = 0.0219);
MVP		0.41
MPC		0.40
ClinPred		0.32	T
GERP RS		2.6
Varity_R		0.070
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-102866809;