9-98736542-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_173551.5(ANKS6):c.2593C>T(p.Pro865Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000491 in 1,612,498 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: ANKS6 NM_173551.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.74

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074454546).
• BP6: Variant 9-98736542-G-A is Benign according to our data. Variant chr9-98736542-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 390055.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKS6	NM_173551.5	c.2593C>T	p.Pro865Ser	missense_variant	15/15	ENST00000353234.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKS6	ENST00000353234.5	c.2593C>T	p.Pro865Ser	missense_variant	15/15	1	NM_173551.5	P1
ANKS6	ENST00000375019.6	c.1690C>T	p.Pro564Ser	missense_variant	14/15	5
ANKS6	ENST00000444472.5	c.1003C>T	p.Pro335Ser	missense_variant	8/9	2
ANKS6	ENST00000634393.1	n.1728C>T		non_coding_transcript_exon_variant	14/15	5

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00849

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00113 AC: 280 AN: 247076 Hom.: 3 AF XY: 0.00114 AC XY: 153 AN XY: 134140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00520

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.000462

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000482 AC: 704 AN: 1460226 Hom.: 7 Cov.: 32 AF XY: 0.000486 AC XY: 353 AN XY: 726106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00506

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.000790

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.000879

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74444

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00851

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000917 Hom.: 1

Bravo AF: 0.000593

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00106 AC: 128

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 20, 2016

The P865S variant in the ANKS6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the P865S variant was observed on 97 of 7922 alleles (1.2%) from individuals of East Asian background, in the Exome Aggregation Consortium (ExAC) data set, indicating it may be a rare variant in this population. The P865S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P865S as a variant of uncertain significance. -

Nephronophthisis 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0074	T;T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	0.81	D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.7	D;N
REVEL	Benign	0.21
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.31	T;T
Polyphen		1.0	.;D
Vest4		0.52
MVP		0.80
MPC		0.52
ClinPred		0.066	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.82

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

Other links and lift over

dbSNP: rs199851177; hg19: chr9-101498824;