9-98770938-C-T

Position:

• chr9-98770938-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173551.5(ANKS6):​c.1930G>A​(p.Val644Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 1,586,358 control chromosomes in the GnomAD database, including 720,902 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (68030 hom., cov: 34)
  • Exomes 𝑓: 0.95 (652872 hom.)
• Consequence: ANKS6 NM_173551.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.31

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=6.176339E-7).
• BP6: Variant 9-98770938-C-T is Benign according to our data. Variant chr9-98770938-C-T is described in ClinVar as [Benign]. Clinvar id is 262847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKS6	NM_173551.5	c.1930G>A	p.Val644Ile	missense_variant	10/15	ENST00000353234.5	NP_775822.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKS6	ENST00000353234.5	c.1930G>A	p.Val644Ile	missense_variant	10/15	1	NM_173551.5	ENSP00000297837	P1
ANKS6	ENST00000375019.6	c.1027G>A	p.Val343Ile	missense_variant	9/15	5		ENSP00000364159
ANKS6	ENST00000444472.5	c.337G>A	p.Val113Ile	missense_variant	3/9	2		ENSP00000398648
ANKS6	ENST00000634393.1	n.1030G>A		non_coding_transcript_exon_variant	8/15	5

Frequencies

GnomAD3 genomes AF: 0.944 AC: 143596 AN: 152180 Hom.: 67989 Cov.: 34

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.868

Gnomad FIN AF: 0.990

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.966

Gnomad OTH AF: 0.942

GnomAD3 exomes AF: 0.919 AC: 211326 AN: 229872 Hom.: 98015 AF XY: 0.924 AC XY: 115255 AN XY: 124798

Gnomad AFR exome AF: 0.953

Gnomad AMR exome AF: 0.800

Gnomad ASJ exome AF: 0.951

Gnomad EAS exome AF: 0.718

Gnomad SAS exome AF: 0.888

Gnomad FIN exome AF: 0.992

Gnomad NFE exome AF: 0.968

Gnomad OTH exome AF: 0.943

GnomAD4 exome AF: 0.953 AC: 1366317 AN: 1434060 Hom.: 652872 Cov.: 68 AF XY: 0.952 AC XY: 677690 AN XY: 712228

Gnomad4 AFR exome AF: 0.956

Gnomad4 AMR exome AF: 0.813

Gnomad4 ASJ exome AF: 0.948

Gnomad4 EAS exome AF: 0.733

Gnomad4 SAS exome AF: 0.885

Gnomad4 FIN exome AF: 0.992

Gnomad4 NFE exome AF: 0.969

Gnomad4 OTH exome AF: 0.947

GnomAD4 genome AF: 0.943 AC: 143690 AN: 152298 Hom.: 68030 Cov.: 34 AF XY: 0.941 AC XY: 70062 AN XY: 74458

Gnomad4 AFR AF: 0.953

Gnomad4 AMR AF: 0.881

Gnomad4 ASJ AF: 0.948

Gnomad4 EAS AF: 0.719

Gnomad4 SAS AF: 0.868

Gnomad4 FIN AF: 0.990

Gnomad4 NFE AF: 0.966

Gnomad4 OTH AF: 0.940

Alfa AF: 0.954 Hom.: 164064

Bravo AF: 0.934

TwinsUK AF: 0.965 AC: 3577

ALSPAC AF: 0.964 AC: 3717

ESP6500AA AF: 0.955 AC: 3644

ESP6500EA AF: 0.967 AC: 7978

ExAC AF: 0.921 AC: 111266

Asia WGS AF: 0.828 AC: 2878 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 16 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.4
DANN	Benign	0.82
DEOGEN2	Benign	0.0075	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	6.2e-7	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.035	.;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.070
Sift	Benign	1.0	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0	.;B
Vest4		0.031
MPC		0.082
ClinPred		0.00073	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.11

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: rs6415847; hg19: chr9-101533220; COSMIC: COSV62050816;