11-113399438-A-G

Variant names:

• chr11-113399438-A-G
• rs2734849
• NM_178510.2:c.1469A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_178510.2(ANKK1):​c.1469A>G​(p.His490Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 1,596,064 control chromosomes in the GnomAD database, including 177,903 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.37 (12138 hom., cov: 33)
  • Exomes 𝑓: 0.47 (165765 hom.)
• Consequence: ANKK1 NM_178510.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.500
• Publications: 91 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.7886806E-5).
• BP6: Variant 11-113399438-A-G is Benign according to our data. Variant chr11-113399438-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060675.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178510.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKK1	NM_178510.2	MANE Select	c.1469A>G	p.His490Arg	missense	Exon 8 of 8	NP_848605.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKK1	ENST00000303941.4	TSL:1 MANE Select	c.1469A>G	p.His490Arg	missense	Exon 8 of 8	ENSP00000306678.3

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55676 AN: 151902 Hom.: 12150 Cov.: 33

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.0612

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.387 AC: 85778 AN: 221404 AF XY: 0.400

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.0562

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.467 AC: 674674 AN: 1444042 Hom.: 165765 Cov.: 106 AF XY: 0.466 AC XY: 333989 AN XY: 716418

African (AFR) AF: 0.152 AC: 5039 AN: 33146

American (AMR) AF: 0.245 AC: 10391 AN: 42386

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 12863 AN: 25788

East Asian (EAS) AF: 0.0595 AC: 2324 AN: 39064

South Asian (SAS) AF: 0.366 AC: 30486 AN: 83240

European-Finnish (FIN) AF: 0.463 AC: 23799 AN: 51386

Middle Eastern (MID) AF: 0.438 AC: 2519 AN: 5750

European-Non Finnish (NFE) AF: 0.508 AC: 560800 AN: 1103516

Other (OTH) AF: 0.443 AC: 26453 AN: 59766

GnomAD4 genome AF: 0.366 AC: 55667 AN: 152022 Hom.: 12138 Cov.: 33 AF XY: 0.360 AC XY: 26779 AN XY: 74294

African (AFR) AF: 0.164 AC: 6808 AN: 41490

American (AMR) AF: 0.306 AC: 4678 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1685 AN: 3464

East Asian (EAS) AF: 0.0608 AC: 312 AN: 5134

South Asian (SAS) AF: 0.339 AC: 1630 AN: 4814

European-Finnish (FIN) AF: 0.444 AC: 4698 AN: 10588

Middle Eastern (MID) AF: 0.448 AC: 129 AN: 288

European-Non Finnish (NFE) AF: 0.506 AC: 34353 AN: 67944

Other (OTH) AF: 0.406 AC: 858 AN: 2114

Alfa AF: 0.459 Hom.: 76495

Bravo AF: 0.347

TwinsUK AF: 0.509 AC: 1886

ALSPAC AF: 0.518 AC: 1998

ESP6500AA AF: 0.164 AC: 665

ESP6500EA AF: 0.502 AC: 4205

ExAC AF: 0.377 AC: 45379

Asia WGS AF: 0.185 AC: 643 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ANKK1-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0070
DANN	Benign	0.18
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.000048	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.8	N
PhyloP100		-0.50
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.088
Sift	Benign	0.77	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.071
ClinPred		0.026	T
GERP RS		-9.3
Varity_R		0.042
gMVP		0.097
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2734849; hg19: chr11-113270160; COSMIC: COSV58273222; COSMIC: COSV58273222;