rs776931798

chr9-98782510-A-Cchr9-98782510-A-G

Variant summary

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

The NM_173551.5(ANKS6):c.1176T>G(p.Asn392Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ANKS6 NM_173551.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.184

Genes affected

ANKS6 (HGNC:26724): (ankyrin repeat and sterile alpha motif domain containing 6) This gene encodes a protein containing multiple ankyrin repeats and a SAM domain. It is thought that this protein may localize to the proximal region of the primary cilium, and may play a role in renal and cardiovascular development. Mutations in this gene have been shown to cause a form of nephronophthisis (NPHP16), a chronic tubulo-interstitial nephritis. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKS6	NM_173551.5	c.1176T>G	p.Asn392Lys	missense_variant	5/15	ENST00000353234.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKS6	ENST00000353234.5	c.1176T>G	p.Asn392Lys	missense_variant	5/15	1	NM_173551.5	P1
ANKS6	ENST00000375019.6	c.273T>G	p.Asn91Lys	missense_variant	4/15	5
ANKS6	ENST00000634393.1	n.276T>G		non_coding_transcript_exon_variant	3/15	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 392 of the ANKS6 protein (p.Asn392Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ANKS6-related conditions. ClinVar contains an entry for this variant (Variation ID: 541401). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.22
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.76
MutPred		0.53		.;Loss of ubiquitination at K391 (P = 0.0547);
MVP		0.44
MPC		0.41
ClinPred		0.99	D
GERP RS		-5.2
Varity_R		0.35
gMVP		0.57

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: rs776931798; hg19: chr9-101544792;