chr9-98768110-G-A

Position:

chr9-98768110-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_173551.5(ANKS6):c.2113C>T(p.Pro705Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000583 in 1,612,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ANKS6
NM_173551.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.12

Variant links:

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 links:

ANKS6 (HGNC:):

ANKS6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013428092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKS6	NM_173551.5 linkuse as main transcript	c.2113C>T	p.Pro705Ser	missense_variant	11/15	ENST00000353234.5	NP_775822.3	Q68DC2-1B3KXP1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ANKS6	ENST00000353234.5 linkuse as main transcript	c.2113C>T	p.Pro705Ser	missense_variant	11/15	1	NM_173551.5	ENSP00000297837.6	Q68DC2-1
ANKS6	ENST00000375019.6 linkuse as main transcript	c.1210C>T	p.Pro404Ser	missense_variant	10/15	5		ENSP00000364159.2	A0A0A0MRS7
ANKS6	ENST00000444472.5 linkuse as main transcript	c.517C>T	p.Pro173Ser	missense_variant	4/9	2		ENSP00000398648.1	H7C163
ANKS6	ENST00000634393.1 linkuse as main transcript	n.1213C>T		non_coding_transcript_exon_variant	9/15	5

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000937

AC:

AN:

245540

Hom.:

AF XY:

0.0000600

AC XY:

AN XY:

133378

show subpopulations

Gnomad AFR exome

AF:

0.00147

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1459756

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726066

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000341

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000865

Hom.:

Bravo

AF:

0.000408

ESP6500AA

AF:

0.00233

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephronophthisis 16

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 17, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2022	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 705 of the ANKS6 protein (p.Pro705Ser). This variant is present in population databases (rs146038901, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with ANKS6-related conditions. ClinVar contains an entry for this variant (Variation ID: 566534). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2024

The c.2113C>T (p.P705S) alteration is located in exon 11 (coding exon 11) of the ANKS6 gene. This alteration results from a C to T substitution at nucleotide position 2113, causing the proline (P) at amino acid position 705 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ANKS6-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2024

The ANKS6 c.2113C>T variant is predicted to result in the amino acid substitution p.Pro705Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.0062

.;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

.;L

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.75

N;N

REVEL

Benign

0.11

Sift

Benign

0.23

T;T

Sift4G

Benign

0.77

T;T

Polyphen

0.36

.;B

Vest4

0.18

MVP

0.69

MPC

0.10

ClinPred

0.030

GERP RS

4.0

Varity_R

0.021

gMVP

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over