9-98756549-T-G

Position:

chr9-98756549-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173551.5(ANKS6):c.2197A>C(p.Thr733Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,587,758 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 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ANKS6
NM_173551.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.36

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21750978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKS6	NM_173551.5 linkuse as main transcript	c.2197A>C	p.Thr733Pro	missense_variant	12/15	ENST00000353234.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKS6	ENST00000353234.5 linkuse as main transcript	c.2197A>C	p.Thr733Pro	missense_variant	12/15	1	NM_173551.5	P1	Q68DC2-1
ANKS6	ENST00000375019.6 linkuse as main transcript	c.1294A>C	p.Thr432Pro	missense_variant	11/15	5
ANKS6	ENST00000444472.5 linkuse as main transcript	c.607A>C	p.Thr203Pro	missense_variant	5/9	2
ANKS6	ENST00000634393.1 linkuse as main transcript	n.1297A>C		non_coding_transcript_exon_variant	10/15	5

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000104

AC:

AN:

220312

Hom.:

AF XY:

0.000109

AC XY:

AN XY:

119152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000678

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000161

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

160

AN:

1435648

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

712850

show subpopulations

Gnomad4 AFR exome

AF:

0.000156

Gnomad4 AMR exome

AF:

0.0000500

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000147

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000202

GnomAD4 genome

AF:

0.000131

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000710

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.0000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	Has not been previously published as pathogenic or benign to our knowledge -

Nephronophthisis 16

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 09, 2022

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 733 of the ANKS6 protein (p.Thr733Pro). This variant is present in population databases (rs201419783, gnomAD 0.02%). 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: 579133). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2021

The c.2197A>C (p.T733P) alteration is located in exon 12 (coding exon 12) of the ANKS6 gene. This alteration results from a A to C substitution at nucleotide position 2197, causing the threonine (T) at amino acid position 733 to be replaced by a proline (P). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.22

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.81

.;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.31

Sift

Benign

0.095

T;T

Sift4G

Benign

0.085

T;T

Polyphen

1.0

.;D

Vest4

0.59

MVP

0.79

MPC

0.54

ClinPred

0.42

GERP RS

5.4

Varity_R

0.71

gMVP

0.33

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