chr9-98778412-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_173551.5(ANKS6):​c.1381C>T​(p.Arg461Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ANKS6
NM_173551.5 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-98778412-G-A is Pathogenic according to our data. Variant chr9-98778412-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 579608.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ANKS6NM_173551.5 linkuse as main transcriptc.1381C>T p.Arg461Ter stop_gained 7/15 ENST00000353234.5 NP_775822.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ANKS6ENST00000353234.5 linkuse as main transcriptc.1381C>T p.Arg461Ter stop_gained 7/151 NM_173551.5 ENSP00000297837 P1Q68DC2-1
ANKS6ENST00000375019.6 linkuse as main transcriptc.478C>T p.Arg160Ter stop_gained 6/155 ENSP00000364159
ANKS6ENST00000634393.1 linkuse as main transcriptn.481C>T non_coding_transcript_exon_variant 5/155

Frequencies

GnomAD3 genomes
AF:
0.000230
AC:
35
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.0362
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000804
AC:
2
AN:
248904
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135122
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:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461624
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727110
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000230
AC:
35
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
15
AN XY:
74332
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000373
Hom.:
0
Bravo
AF:
0.000306
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000237
AC:
2
ExAC
AF:
0.00000826
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Nephronophthisis 16 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 07, 2017For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ANKS6 are known to be pathogenic (PMID: 23793029, 25599650). This variant has not been reported in the literature in individuals with ANKS6-related disease. This variant is present in population databases (rs369437168, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Arg461*) in the ANKS6 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.92
D
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.28
GERP RS
3.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs369437168; hg19: chr9-101540694; API