rs745881769

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_173551.5(ANKS6):c.193G>T(p.Val65Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,264,420 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 10 hom. )

Consequence

ANKS6
NM_173551.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.640

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

nephronophthisis 16
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
nephronophthisis 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nephronophthisis 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ANKS6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005586326).

BP6

Variant 9-98796299-C-A is Benign according to our data. Variant chr9-98796299-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474447.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKS6	NM_173551.5 link	c.193G>T	p.Val65Phe	missense_variant	Exon 1 of 15	ENST00000353234.5	NP_775822.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ANKS6	ENST00000353234.5 link	c.193G>T	p.Val65Phe	missense_variant	Exon 1 of 15	1	NM_173551.5	ENSP00000297837.6
ANKS6	ENST00000471846.1 link	n.241G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
ANKS6	ENST00000375019.6 link	c.-42+385G>T		intron_variant	Intron 1 of 14	5		ENSP00000364159.2

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

298

AN:

150438

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000606

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00126

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00336

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00436

GnomAD2 exomes

AF:

0.00377

AC:

AN:

12730

AF XY:

0.00408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00934

Gnomad NFE exome

AF:

0.00437

Gnomad OTH exome

AF:

0.00226

GnomAD4 exome

AF:

0.00297

AC:

3312

AN:

1113874

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

1562

AN XY:

533436

show subpopulations

African (AFR)

AF:

0.000172

AC:

AN:

23320

American (AMR)

AF:

0.000509

AC:

AN:

11784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15394

East Asian (EAS)

AF:

0.000230

AC:

AN:

26054

South Asian (SAS)

AF:

0.00277

AC:

AN:

29240

European-Finnish (FIN)

AF:

0.00575

AC:

134

AN:

23308

Middle Eastern (MID)

AF:

0.00165

AC:

AN:

3034

European-Non Finnish (NFE)

AF:

0.00318

AC:

2981

AN:

937158

Other (OTH)

AF:

0.00213

AC:

AN:

44582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00198

AC:

298

AN:

150546

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

138

AN XY:

73456

show subpopulations

African (AFR)

AF:

0.000604

AC:

AN:

41394

American (AMR)

AF:

0.00126

AC:

AN:

15132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.00228

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00336

AC:

AN:

10120

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00293

AC:

197

AN:

67184

Other (OTH)

AF:

0.00431

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00217

Hom.:

Bravo

AF:

0.00180

ExAC

AF:

0.00113

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.193G>T (p.V65F) alteration is located in exon 1 (coding exon 1) of the ANKS6 gene. This alteration results from a G to T substitution at nucleotide position 193, causing the valine (V) at amino acid position 65 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Nephronophthisis 16

Benign:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANKS6-related disorder

Benign:1

Aug 19, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.2

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.011

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.98

LIST_S2

Benign

0.41

M_CAP

Benign

0.0049

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

PhyloP100

-0.64

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.62

Sift

Benign

0.14

Sift4G

Benign

0.10

Vest4

0.33

ClinPred

0.016

GERP RS

0.71

PromoterAI

0.010

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.14

gMVP

0.43

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over