11-113395358-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_178510.2(ANKK1):c.633-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,902 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 20 hom. )

Consequence

ANKK1
NM_178510.2 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.76

Variant links:

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]

ANKK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 5: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen, phyloP100way_vertebrate [when BayesDel_addAF, MutationTaster was below the threshold]

BP6

Variant 11-113395358-G-T is Benign according to our data. Variant chr11-113395358-G-T is described in ClinVar as [Benign]. Clinvar id is 783648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00745 (1134/152242) while in subpopulation AFR AF = 0.0265 (1099/41536). AF 95% confidence interval is 0.0252. There are 14 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKK1	NM_178510.2 link	c.633-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 7	ENST00000303941.4	NP_848605.1	Q8NFD2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKK1	ENST00000303941.4 link	c.633-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 7	1	NM_178510.2	ENSP00000306678.3		Q8NFD2
ANKK1	ENST00000542948.1 link	n.*187-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 4	3		ENSP00000445810.1		H0YH32

Frequencies

GnomAD3 genomes

AF:

0.00746

AC:

1135

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.00194

AC:

484

AN:

249230

AF XY:

0.00158

show subpopulations

Gnomad AFR exome

AF:

0.0271

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000885

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.000697

AC:

1019

AN:

1461660

Hom.:

Cov.:

AF XY:

0.000624

AC XY:

454

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0251

AC:

840

AN:

33474

Gnomad4 AMR exome

AF:

0.00165

AC:

AN:

44718

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000232

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53402

Gnomad4 NFE exome

AF:

0.0000126

AC:

AN:

1111838

Gnomad4 Remaining exome

AF:

0.00137

AC:

AN:

60370

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00745

AC:

1134

AN:

152242

Hom.:

Cov.:

AF XY:

0.00748

AC XY:

557

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0265

AC:

0.026459

AN:

0.026459

Gnomad4 AMR

AF:

0.00131

AC:

0.00130702

AN:

0.00130702

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000103

AC:

0.000102923

AN:

0.000102923

Gnomad4 OTH

AF:

0.00380

AC:

0.00380228

AN:

0.00380228

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00808

ESP6500AA

AF:

0.0250

AC:

ESP6500EA

AF:

0.000363

AC:

ExAC

AF:

0.00244

AC:

295

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ANKK1-related disorder

Benign:1

Apr 06, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

GERP RS

4.4

Mutation Taster

=0/100

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.99

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over