rs148071928

Positions:

• chr9-98778228-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_173551.5(ANKS6):​c.1565A>G​(p.Asn522Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,614,068 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: ANKS6 NM_173551.5 missense, splice_region
• Scores: Splicing: ADA: 0.0004231
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.332

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037843883).
• BP6: Variant 9-98778228-T-C is Benign according to our data. Variant chr9-98778228-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 541404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKS6	NM_173551.5	c.1565A>G	p.Asn522Ser	missense_variant, splice_region_variant	7/15	ENST00000353234.5	NP_775822.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKS6	ENST00000353234.5	c.1565A>G	p.Asn522Ser	missense_variant, splice_region_variant	7/15	1	NM_173551.5	ENSP00000297837	P1
ANKS6	ENST00000375019.6	c.662A>G	p.Asn221Ser	missense_variant, splice_region_variant	6/15	5		ENSP00000364159
ANKS6	ENST00000634393.1	n.665A>G		splice_region_variant, non_coding_transcript_exon_variant	5/15	5

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 342 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00262 AC: 652 AN: 249252 Hom.: 1 AF XY: 0.00276 AC XY: 373 AN XY: 135250

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000870

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00478

Gnomad NFE exome AF: 0.00429

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00261 AC: 3816 AN: 1461808 Hom.: 6 Cov.: 31 AF XY: 0.00257 AC XY: 1870 AN XY: 727194

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00511

Gnomad4 NFE exome AF: 0.00298

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74456

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00314 Hom.: 4

Bravo AF: 0.00185

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00102 AC: 4

ESP6500EA AF: 0.00337 AC: 28

ExAC AF: 0.00324 AC: 392

EpiCase AF: 0.00463

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

ANKS6: BP4 -

ANKS6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 08, 2020

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	0.053
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.7
DANN	Benign	0.24
DEOGEN2	Benign	0.0056	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.029
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0030	.;B
Vest4		0.15
MVP		0.29
MPC		0.080
ClinPred		0.00081	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.022
gMVP		0.060

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.19
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: rs148071928; hg19: chr9-101540510;