rs745881769

Positions:

• chr9-98796299-C-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.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. 15/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.640

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 474447.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr9-98796299-C-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKS6	NM_173551.5	c.193G>T	p.Val65Phe	missense_variant	1/15	ENST00000353234.5	NP_775822.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKS6	ENST00000353234.5	c.193G>T	p.Val65Phe	missense_variant	1/15	1	NM_173551.5	ENSP00000297837.6
ANKS6	ENST00000375019.6	c.-42+385G>T		intron_variant		5		ENSP00000364159.2
ANKS6	ENST00000471846.1	n.241G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 298 AN: 150438 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.00377 AC: 48 AN: 12730 Hom.: 1 AF XY: 0.00408 AC XY: 31 AN XY: 7598

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 SAS exome AF: 0.00570

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.: 10 Cov.: 30 AF XY: 0.00293 AC XY: 1562 AN XY: 533436

Gnomad4 AFR exome AF: 0.000172

Gnomad4 AMR exome AF: 0.000509

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000230

Gnomad4 SAS exome AF: 0.00277

Gnomad4 FIN exome AF: 0.00575

Gnomad4 NFE exome AF: 0.00318

Gnomad4 OTH exome AF: 0.00213

GnomAD4 genome AF: 0.00198 AC: 298 AN: 150546 Hom.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 138 AN XY: 73456

Gnomad4 AFR AF: 0.000604

Gnomad4 AMR AF: 0.00126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00336

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00431

Alfa AF: 0.00217 Hom.: 0

Bravo AF: 0.00180

ExAC AF: 0.00113 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

ANKS6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2019

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	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.2
DANN	Benign	0.60
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.067
Sift	Benign	0.14	T
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.33
MVP		0.57
MPC		0.17
ClinPred		0.016	T
GERP RS		0.71
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.14
gMVP		0.43

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

Other links and lift over

dbSNP: rs745881769; hg19: chr9-101558581;