chr11-113399438-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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=4.7886806E-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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKK1	NM_178510.2	c.1469A>G	p.His490Arg	missense_variant	Exon 8 of 8	ENST00000303941.4	NP_848605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKK1	ENST00000303941.4	c.1469A>G	p.His490Arg	missense_variant	Exon 8 of 8	1	NM_178510.2	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

GnomAD3 exomes AF: 0.387 AC: 85778 AN: 221404 Hom.: 19003 AF XY: 0.400 AC XY: 47893 AN XY: 119796

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 SAS exome AF: 0.363

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

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.0595

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.463

Gnomad4 NFE exome AF: 0.508

Gnomad4 OTH exome AF: 0.443

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

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.306

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.0608

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.506

Gnomad4 OTH AF: 0.406

Alfa AF: 0.479 Hom.: 41465

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 v4.3

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
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

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