chr9-98780235-T-C

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.1322A>G(p.Gln441Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,614,084 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 11 hom. )

Consequence

ANKS6
NM_173551.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:3

Conservation

PhyloP100: 1.78

Publications

4 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=0.009947628).

BP6

Variant 9-98780235-T-C is Benign according to our data. Variant chr9-98780235-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 64355.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKS6	NM_173551.5 link	c.1322A>G	p.Gln441Arg	missense_variant	Exon 6 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.1322A>G	p.Gln441Arg	missense_variant	Exon 6 of 15	1	NM_173551.5	ENSP00000297837.6	Q68DC2-1
ANKS6	ENST00000375019.6 link	c.419A>G	p.Gln140Arg	missense_variant	Exon 5 of 15	5		ENSP00000364159.2	A0A0A0MRS7
ANKS6	ENST00000634393.1 link	n.422A>G		non_coding_transcript_exon_variant	Exon 4 of 15	5

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000752

AC:

187

AN:

248722

AF XY:

0.000874

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000798

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000355

AC:

519

AN:

1461720

Hom.:

Cov.:

AF XY:

0.000503

AC XY:

366

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00500

AC:

431

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111982

Other (OTH)

AF:

0.000480

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000184

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41592

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00373

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000927

AC:

112

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nephronophthisis 16

Pathogenic:2Uncertain:1Benign:3

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

NM_173551.3:c.1322A>G in the ANKS6 gene has an allele frequency of 0.006 in South Asian subpopulation in the gnomAD database. The FKTN c.1322A>G (p.Gln441Arg) variant has been detected in a family with polycystic kidney disease in homozygous state (PMID: 23793029). Functional studies revealed that p.Gln441Arg was deleterious for protein function (PMID: 23793029). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor and MutationTaster. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3; PS3; PP3. -

Aug 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Aug 07, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

.;T

Eigen

Benign

0.029

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.0099

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

1.8

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.075

Sift

Benign

0.10

T;T

Sift4G

Uncertain

0.025

D;D

Polyphen

0.80

.;P

Vest4

0.80

MVP

0.79

MPC

0.13

ClinPred

0.017

GERP RS

1.9

Varity_R

0.051

gMVP

0.45

Mutation Taster

=90/10

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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chr9-98780235-T-C

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