Genetic Variant ANKS6:p.Asp313Tyr (chr9-98784128-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_173551.5(ANKS6):c.937G>T(p.Asp313Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,405,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D313N) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ANKS6
NM_173551.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.25

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

nephronophthisis 16
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
nephronophthisis 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nephronophthisis 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ANKS6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-98784127-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 996118.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173551.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKS6	NM_173551.5	MANE Select	c.937G>T	p.Asp313Tyr	missense	Exon 4 of 15	NP_775822.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANKS6	ENST00000353234.5	TSL:1 MANE Select	c.937G>T	p.Asp313Tyr	missense	Exon 4 of 15	ENSP00000297837.6
ANKS6	ENST00000941017.1		c.937G>T	p.Asp313Tyr	missense	Exon 4 of 13	ENSP00000611076.1
ANKS6	ENST00000927508.1		c.937G>T	p.Asp313Tyr	missense	Exon 4 of 13	ENSP00000597567.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000140

AC:

AN:

214910

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000997

Gnomad OTH exome

AF:

0.000200

GnomAD4 exome

AF:

0.00000285

AC:

AN:

1405654

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31820

American (AMR)

AF:

0.00

AC:

AN:

39006

Ashkenazi Jewish (ASJ)

AF:

0.0000415

AC:

AN:

24072

East Asian (EAS)

AF:

0.00

AC:

AN:

37616

South Asian (SAS)

AF:

0.00

AC:

AN:

79324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5552

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077880

Other (OTH)

AF:

0.0000173

AC:

AN:

57870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.3

PhyloP100

7.3

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.71

MutPred

0.43

Gain of phosphorylation at D313 (P = 0.0317)

MVP

0.82

MPC

0.57

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.50

gMVP

0.60

Mutation Taster

=52/48

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over