rs587777025

chr9-98751050-CTGA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_173551.5(ANKS6):c.2370_2372del(p.Tyr790_Gln791delinsTer) variant causes a stop gained, inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,610,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ANKS6 NM_173551.5 stop_gained, inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.25

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 Pathogenic. Variant got 18 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 9-98751050-CTGA-C is Pathogenic according to our data. Variant chr9-98751050-CTGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 64358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKS6	NM_173551.5	c.2370_2372del	p.Tyr790_Gln791delinsTer	stop_gained, inframe_deletion	13/15	ENST00000353234.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKS6	ENST00000353234.5	c.2370_2372del	p.Tyr790_Gln791delinsTer	stop_gained, inframe_deletion	13/15	1	NM_173551.5	P1
ANKS6	ENST00000375019.6	c.1467_1469del	p.Tyr489_Gln490delinsTer	stop_gained, inframe_deletion	12/15	5
ANKS6	ENST00000444472.5	c.778_780del	p.Tyr260_Gln261delinsTer	stop_gained, inframe_deletion	6/9	2
ANKS6	ENST00000634393.1	n.1470_1472del		non_coding_transcript_exon_variant	11/15	5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152000 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000812 AC: 2 AN: 246450 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133476

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: 0.0000683

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1458238 Hom.: 0 AF XY: 0.0000262 AC XY: 19 AN XY: 725122

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: 0.0000588

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152000 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74220

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 16 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 08, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2023	This sequence change creates a premature translational stop signal (p.Tyr790*) in the ANKS6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANKS6 are known to be pathogenic (PMID: 23793029, 25599650). This variant is present in population databases (rs587777025, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 23793029). ClinVar contains an entry for this variant (Variation ID: 64358). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs587777025; hg19: chr9-101513332;