rs11604671

Positions:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
ANKK1	NM_178510.2	c.952G>A	p.Gly318Arg	missense_variant	6/8	ENST00000303941.4	NP_848605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKK1	ENST00000303941.4	c.952G>A	p.Gly318Arg	missense_variant	6/8	1	NM_178510.2	ENSP00000306678	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: no assertion criteria provided

Submissions by phenotype

ANKK1-related disorder Benign:1

Benign, no assertion criteria provided

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;