9-98756543-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173551.5(ANKS6):c.2203C>G(p.Pro735Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,593,224 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (20 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (23 hom.)
• Consequence: ANKS6 NM_173551.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.38

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077734888).
• BP6: Variant 9-98756543-G-C is Benign according to our data. Variant chr9-98756543-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 262848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-98756543-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00879 (1338/152270) while in subpopulation AFR AF= 0.0302 (1254/41548). AF 95% confidence interval is 0.0288. There are 20 homozygotes in gnomad4. There are 653 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKS6	NM_173551.5	c.2203C>G	p.Pro735Ala	missense_variant	12/15	ENST00000353234.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKS6	ENST00000353234.5	c.2203C>G	p.Pro735Ala	missense_variant	12/15	1	NM_173551.5	P1
ANKS6	ENST00000375019.6	c.1300C>G	p.Pro434Ala	missense_variant	11/15	5
ANKS6	ENST00000444472.5	c.613C>G	p.Pro205Ala	missense_variant	5/9	2
ANKS6	ENST00000634393.1	n.1303C>G		non_coding_transcript_exon_variant	10/15	5

Frequencies

GnomAD3 genomes AF: 0.00877 AC: 1335 AN: 152152 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00236 AC: 528 AN: 223366 Hom.: 6 AF XY: 0.00179 AC XY: 217 AN XY: 120988

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00119 AC: 1710 AN: 1440954 Hom.: 23 Cov.: 31 AF XY: 0.00103 AC XY: 737 AN XY: 715990

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.00274

GnomAD4 genome AF: 0.00879 AC: 1338 AN: 152270 Hom.: 20 Cov.: 31 AF XY: 0.00877 AC XY: 653 AN XY: 74454

Gnomad4 AFR AF: 0.0302

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000634 Hom.: 0

Bravo AF: 0.0100

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0273 AC: 110

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00269 AC: 325

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 16 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.21
Sift	Benign	0.036	D;T
Sift4G	Benign	0.090	T;D
Polyphen		1.0	.;D
Vest4		0.72
MVP		0.78
MPC		0.51
ClinPred		0.022	T
GERP RS		5.4
Varity_R		0.20
gMVP		0.33

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: rs79414550; hg19: chr9-101518825;