rs11604671

Positions:

• chr11-113397337-G-A
• chr11-113397337-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_178510.2(ANKK1):​c.952G>A​(p.Gly318Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,610,528 control chromosomes in the GnomAD database, including 178,724 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.35 (11764 hom., cov: 32)
  • Exomes 𝑓: 0.47 (166960 hom.)
• Consequence: ANKK1 NM_178510.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.81

Genes affected

ANKK1 (HGNC:21027): (ankyrin repeat and kinase domain containing 1) The protein encoded by this gene belongs to the Ser/Thr protein kinase family, and protein kinase superfamily involved in signal transduction pathways. This gene is closely linked to DRD2 gene (GeneID:1813) on chr 11, and a well studied restriction fragment length polymorphism (RFLP) designated TaqIA, was originally associated with the DRD2 gene, however, later was determined to be located in exon 8 of ANKK1 gene (PMIDs: 18621654, 15146457), where it causes a nonconservative amino acid substitution. It is not clear if this gene plays any role in neuropsychiatric disorders previously associated with Taq1A RFLP. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.6214725E-5).
• BP6: Variant 11-113397337-G-A is Benign according to our data. Variant chr11-113397337-G-A is described in ClinVar as [Benign]. Clinvar id is 3060965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKK1	NM_178510.2	c.952G>A	p.Gly318Arg	missense_variant	6/8	ENST00000303941.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKK1	ENST00000303941.4	c.952G>A	p.Gly318Arg	missense_variant	6/8	1	NM_178510.2	P1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53357 AN: 151824 Hom.: 11776 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.0609

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.395

GnomAD3 exomes AF: 0.387 AC: 95276 AN: 246430 Hom.: 21550 AF XY: 0.401 AC XY: 53623 AN XY: 133808

Gnomad AFR exome AF: 0.0986

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.0579

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.509

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.465 AC: 678606 AN: 1458586 Hom.: 166960 Cov.: 37 AF XY: 0.465 AC XY: 337172 AN XY: 725656

Gnomad4 AFR exome AF: 0.0972

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.0602

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.464

Gnomad4 NFE exome AF: 0.508

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.351 AC: 53346 AN: 151942 Hom.: 11764 Cov.: 32 AF XY: 0.345 AC XY: 25642 AN XY: 74256

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.483

Gnomad4 EAS AF: 0.0605

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.443

Gnomad4 NFE AF: 0.505

Gnomad4 OTH AF: 0.393

Alfa AF: 0.447 Hom.: 15401

Bravo AF: 0.330

TwinsUK AF: 0.508 AC: 1885

ALSPAC AF: 0.519 AC: 2000

ESP6500AA AF: 0.120 AC: 514

ESP6500EA AF: 0.503 AC: 4269

ExAC AF: 0.391 AC: 47409

Asia WGS AF: 0.182 AC: 634 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ANKK1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.15
DANN	Benign	0.67
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.000046	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.061
Sift	Benign	0.55	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.025
MutPred		0.083		Gain of MoRF binding (P = 0.0254);
MPC		0.070
ClinPred		0.0048	T
GERP RS		0.52
Varity_R		0.033
gMVP		0.12

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: rs11604671; hg19: chr11-113268059; COSMIC: COSV58271548; COSMIC: COSV58271548;