chr9-98736557-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_173551.5(ANKS6):c.2578A>G(p.Ser860Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ANKS6
NM_173551.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.42

Variant links:

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]

ANKS6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31435877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKS6	NM_173551.5 link	c.2578A>G	p.Ser860Gly	missense_variant	Exon 15 of 15	ENST00000353234.5	NP_775822.3	Q68DC2-1B3KXP1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANKS6	ENST00000353234.5 link	c.2578A>G	p.Ser860Gly	missense_variant	Exon 15 of 15	1	NM_173551.5	ENSP00000297837.6	Q68DC2-1
ANKS6	ENST00000375019.6 link	c.1675A>G	p.Ser559Gly	missense_variant	Exon 14 of 15	5		ENSP00000364159.2	A0A0A0MRS7
ANKS6	ENST00000444472.5 link	c.985A>G	p.Ser329Gly	missense_variant	Exon 8 of 9	2		ENSP00000398648.1	H7C163
ANKS6	ENST00000634393.1 link	n.1713A>G		non_coding_transcript_exon_variant	Exon 14 of 15	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000807

AC:

AN:

247678

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134486

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461450

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephronophthisis 16

Uncertain:1

Jun 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 860 of the ANKS6 protein (p.Ser860Gly). This variant is present in population databases (rs780554387, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ANKS6-related conditions. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Inborn genetic diseases

Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2578A>G (p.S860G) alteration is located in exon 15 (coding exon 15) of the ANKS6 gene. This alteration results from a A to G substitution at nucleotide position 2578, causing the serine (S) at amino acid position 860 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

.;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.084

MetaRNN

Benign

0.31

T;T

MetaSVM

Uncertain

-0.091

MutationAssessor

Benign

0.90

.;L

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.033

D;D

Polyphen

0.98

.;D

Vest4

0.55

MutPred

0.14

.;Gain of helix (P = 0.0034);

MVP

0.80

MPC

0.49

ClinPred

0.87

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over