rs377750405

chr9-98780235-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_173551.5(ANKS6):c.1322A>G(p.Gln441Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,614,084 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (11 hom.)
• Consequence: ANKS6 NM_173551.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:1
• Conservation: PhyloP100: 1.78

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009947628).
• BP6: Variant 9-98780235-T-C is Benign according to our data. Variant chr9-98780235-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 64355.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKS6	NM_173551.5	c.1322A>G	p.Gln441Arg	missense_variant	6/15	ENST00000353234.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKS6	ENST00000353234.5	c.1322A>G	p.Gln441Arg	missense_variant	6/15	1	NM_173551.5	P1
ANKS6	ENST00000375019.6	c.419A>G	p.Gln140Arg	missense_variant	5/15	5
ANKS6	ENST00000634393.1	n.422A>G		non_coding_transcript_exon_variant	4/15	5

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000752 AC: 187 AN: 248722 Hom.: 1 AF XY: 0.000874 AC XY: 118 AN XY: 135062

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1461720 Hom.: 11 Cov.: 31 AF XY: 0.000503 AC XY: 366 AN XY: 727124

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74516

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000927 AC: 112

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nephronophthisis 16 Pathogenic:2 Uncertain:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2013	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_173551.3:c.1322A>G in the ANKS6 gene has an allele frequency of 0.006 in South Asian subpopulation in the gnomAD database. The FKTN c.1322A>G (p.Gln441Arg) variant has been detected in a family with polycystic kidney disease in homozygous state (PMID: 23793029). Functional studies revealed that p.Gln441Arg was deleterious for protein function (PMID: 23793029). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor and MutationTaster. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3; PS3; PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 07, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 22, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	0.029
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0099	T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	0.52	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.075
Sift	Benign	0.10	T;T
Sift4G	Uncertain	0.025	D;D
Polyphen		0.80	.;P
Vest4		0.80
MVP		0.79
MPC		0.13
ClinPred		0.017	T
GERP RS		1.9
Varity_R		0.051
gMVP		0.45

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: rs377750405; hg19: chr9-101542517;